WO2025015263A2 - Treating myeloid disorders - Google Patents

Treating myeloid disorders Download PDF

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WO2025015263A2
WO2025015263A2 PCT/US2024/037775 US2024037775W WO2025015263A2 WO 2025015263 A2 WO2025015263 A2 WO 2025015263A2 US 2024037775 W US2024037775 W US 2024037775W WO 2025015263 A2 WO2025015263 A2 WO 2025015263A2
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sf3b1
inhibitor
disorder
myeloid disorder
flt3
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WO2025015263A3 (en
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Virginia M. Shapiro
Kay L. MEDINA
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Mayo Foundation for Medical Education and Research
Mayo Clinic in Florida
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Mayo Foundation for Medical Education and Research
Mayo Clinic in Florida
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • This document relates to methods and materials for treating myeloid disorders (e.g., splicing factor 3B subunit 1 (SF3Bl)-associated myeloid disorders).
  • myeloid disorders e.g., splicing factor 3B subunit 1 (SF3Bl)-associated myeloid disorders.
  • this document provides methods and materials for using one or more inhibitors of early lymphopoiesis to treat a mammal (e.g., a human) having a myeloid disorder (e.g., a SF3B1- associated myeloid disorder).
  • Hematopoiesis is tightly regulated to maintain production of terminally differentiated hematopoietic lineages required for survival. As individuals age, mutations that arise within hematopoietic progenitors can lead to dysregulated hematopoiesis. Dysregulation of myelopoiesis can be either cell-intrinsic or cell-extrinsic. Cell-intrinsic mutations typically result in myelodysplastic syndromes (MDSs) or myeloproliferative disorders (MPNs), while cell-extrinsic systemic inflammation can promote emergency myelopoiesis. However, the cause of the enhanced myelopoiesis is not always clear, and these two mechanisms are not necessarily mutually exclusive. Further, upon additional somatic mutations, both MDSs and MPNs have the potential to progress into acute myeloid leukemia (AML).
  • AML acute myeloid leukemia
  • RNA splicing protein SF3B1 A common mutation in several heterogenous myeloid disorders is in the RNA splicing protein SF3B1 (Mangaonkar et al., Haematologica, 107: 1189-1192 (2022); and Venable et al., Am. J. Clin. Pathol., 156:679-690 (2021)).
  • SF3B1 mutations are found in many subtypes of myeloid disorders (Patnaik et al., Am. J. HematoL, 96:379-394 (2021); Patnaik et al., Am. J.
  • This document provides methods and materials for treating myeloid disorders (e.g., SF3B1 -associated myeloid disorders). For example, this document provides methods and materials for administering one or more inhibitors of early lymphopoiesis to a mammal (e.g., a human) having a myeloid disorder (e.g., a SF3B1 -associated myeloid disorder) to treat the mammal.
  • a mammal e.g., a human
  • a myeloid disorder e.g., a SF3B1 -associated myeloid disorder
  • targeting earlier B-lineage precursor cells can restore normal myelopoiesis and erythropoiesis, and can be used to treat myeloid disorders (e.g., SF3B1- mutated myeloid disorders).
  • one or more inhibitors of early lymphopoiesis can be used treat a mammal (e.g., a human) having a myeloid disorder (e.g., a SF3B1 -associated myeloid disorder).
  • a mammal e.g., a human
  • a myeloid disorder e.g., a SF3B1-associated myeloid disorder
  • Having the ability to treat myeloid disorders as described herein e.g., by administering one or more inhibitors of early lymphopoiesis provides a unique and unrealized opportunity to treat the disease rather than just the symptoms.
  • one aspect of this document features methods for treating a SF3B1- associated myeloid disorder.
  • the methods can include, or consist essentially of, administering an inhibitor of early lymphopoiesis to a mammal identified as having a SF3B1- associated myeloid disorder.
  • the mammal can be a human.
  • the hematopoietic cells of the mammal can express a reduced level of an AFP -binding cassette sub-family B member 7 (ABCB7) polypeptide as compared to the level of expression of said ABCB7 polypeptide by hematopoietic cells of a healthy mammal not having said SF3B1 -associated myeloid disorder.
  • ABS7 AFP -binding cassette sub-family B member 7
  • the SF3B1 -associated myeloid disorder can be a SF3B1 -associated myelodysplastic syndrome.
  • the SF3B1 -associated myeloid disorder can be a SF3B1- associated myeloproliferative disorder.
  • the inhibitor of early lymphopoiesis can be midostaurin, gilteritinib, quizartinib, sorafenib, sunitinib, lestaurtinib, tandutinib, crenolanib, AIU2008, ALLO-819, BGS-2456, BMF-500, CCT245718, CDDD11-8, CHMFL-FLT3-213, CHMFL-FLT3-335, clifutinib besylate, CLN-049, CRBN(FLT3)-8, crenolanib besylate, creserol, CTS-2016, cytarabine/daunorubicin, D-64406, D-65476, danatinib, dapolsertib, E2082-0047, E-6201, EC-70124, EP-0042, ETH-155036, gilteritinib fumarate, H-104, Jil l 8, HD-
  • this document features methods for treating a mammal having a SF3B1 -associated myeloid disorder.
  • the methods can include, or consist essentially of, administering an inhibitor of early lymphopoiesis to a mammal having a SF3B1 -associated myeloid disorder.
  • the mammal can be a human.
  • the hematopoietic cells of the mammal can express a reduced level of an ATP-binding cassette sub-family B member 7 (ABCB7) polypeptide as compared to the level of expression of said ABCB7 polypeptide by hematopoietic cells of a healthy mammal not having said SF3B1 -associated myeloid disorder.
  • ABS7 ATP-binding cassette sub-family B member 7
  • the SF3B1 -associated myeloid disorder can be a SF3B1 -associated myelodysplastic syndrome.
  • the SF3B1 -associated myeloid disorder can be a SF3B1- associated myeloproliferative disorder.
  • the inhibitor of early lymphopoiesis can be midostaurin, gilteritinib, quizartinib, sorafenib, sunitinib, lestaurtinib, tandutinib, crenolanib, AIU2008, ALLO-819, BGS-2456, BMF-500, CCT245718, CDDD11-8, CHMFL-FLT3-213, CHMFL-FLT3-335, clifutinib besylate, CLN-049, CRBN(FLT3)-8, crenolanib besylate, creserol, CTS-2016, cytarabine/daunorubicin, D-64406, D-65476, danatinib, dapolsertib, E2082-0047, E-6201, EC-70124, EP-0042, ETH-155036, gilteritinib fumarate, H-104, H- 118, HD-
  • this document features uses of a composition comprising an inhibitor of early lymphopoiesis to treat a SF3B1 -associated myeloid disorder.
  • the SF3B1- associated myeloid disorder can be a SF3B1 -associated myelodysplastic syndrome.
  • the SF3B1 -associated myeloid disorder can be a SF3B1 -associated myeloproliferative disorder.
  • the inhibitor of early lymphopoiesis can be midostaurin, gilteritinib, quizartinib, sorafenib, sunitinib, lestaurtinib, tandutinib, crenolanib, AIU2008, ALLO-819, BGS-2456, BMF-500, CCT245718, CDDD11-8, CHMFL-FLT3-213, CHMFL-FLT3-335, clifutinib besylate, CLN- 049, CRBN(FLT3)-8, crenolanib besylate, creserol, CTS-2016, cytarabine/daunorubicin, D- 64406, D-65476, danatinib, dapolsertib, E2082-0047, E-6201, EC-70124, EP-0042, ETH- 155036, gilteritinib fumarate, H-104, H-118,
  • this document features inhibitors of early lymphopoiesis for use in the preparation of a medicament to treat a SF3B1 -associated myeloid disorder.
  • the SF3B1- associated myeloid disorder can be a SF3B1 -associated myelodysplastic syndrome.
  • the SF3B1 -associated myeloid disorder can be a SF3B1 -associated myeloproliferative disorder.
  • the inhibitor of early lymphopoiesis can be midostaurin, gilteritinib, quizartinib, sorafenib, sunitinib, lestaurtinib, tandutinib, crenolanib, AIU2008, ALLO-819, BGS-2456, BMF-500, CCT245718, CDDD11-8, CHMFL-FLT3-213, CHMFL-FLT3-335, clifutinib besylate, CLN- 049, CRBN(FLT3)-8, crenolanib besylate, creserol, CTS-2016, cytarabine/daunorubicin, D- 64406, D-65476, danatinib, dapolsertib, E2082-0047, E-6201, EC-70124, EP-0042, ETH- 155036, gilteritinib fumarate, H-104, H-118,
  • this document features inhibitors of early lymphopoiesis for use in the treatment of a SF3B1 -associated myeloid disorder.
  • the SF3B1 -associated myeloid disorder can be a SF3B1 -associated myelodysplastic syndrome.
  • the SF3B1 -associated myeloid disorder can be a SF3B1 -associated myeloproliferative disorder.
  • the inhibitor of early lymphopoiesis can be midostaurin, gilteritinib, quizartinib, sorafenib, sunitinib, lestaurtinib, tandutinib, crenolanib, AIU2008, ALLO-819, BGS-2456, BMF-500, CCT245718, CDDD11-8, CHMFL-FLT3-213, CHMFL-FLT3-335, clifutinib besylate, CLN- 049, CRBN(FLT3)-8, crenolanib besylate, creserol, CTS-2016, cytarabine/daunorubicin, D- 64406, D-65476, danatinib, dapolsertib, E2082-0047, E-6201, EC-70124, EP-0042, ETH- 155036, gilteritinib fumarate, H-104, H-118,
  • Figure 1 A schematic showing that depletion of ABCB7 in the B-cell lineage leads to cell-extrinsic emergency myelopoiesis.
  • Figures 2A-2D B cell development was blocked at the pro-B cell stage in mbl-cre ABCB7 cKO mice.
  • Figure 2A A representative FACS analysis of the Hardy fractions between WT, mbl-cre ABCB7 cKO, and CD23-cre ABCB7 cKO mice in the bone marrow.
  • Figure 2B Representative data of splenic B cell populations from WT, mbl-cre ABCB7 cKO, and CD23-cre ABCB7 cKO mice.
  • Figures 2C-2D Quantitation of Hardy Fractions (Figure 2C) and splenic B cells (Figure 2D) from WT, mbl-cre ABCB7 cKO, and CD23-cre ABCB7 cKO mice. Data are representative of at least 5 mice per group. *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001, **** p ⁇ 0.0001, ns, not significant.
  • Figure 3 Analysis of pro-B cell iron in WT and mbl-cre ABCB7 cKO mice. Pro-B cells from WT and mbl-cre ABCB7 cKO mice were analyzed for Phen Green quenching for intracellular iron overload.
  • Figures 4A-4D ABCB7-deficient pro-B cells had replication induced DNA damage.
  • Figures 4A-4B Bone marrow suspensions were incubated for 3 hours with EdU analyzed by FACS analysis along with phosphoH2A.X ( Figure 4A) and quantified across experiments ( Figure 4B).
  • Figures 4C-4D Percent and MFI of EdU + cells after 3 hours of labeling are shown in ( Figure 4C) and quantified in ( Figure 4D).
  • Figure 5 H&E of bone marrow from older/sick CD2-icre ABCB7 cKO mice as compared to age-matched WT or littermate controls.
  • Figure 6 Analysis of erythropoiesis using CD71 and Teri 19 in CD2-icre ABCB7 cKO mice as compared to age-matched WT or littermate controls.
  • Figure 7 CBC analysis of 4-5-month CD2-icre ABCB7 cKO mice as compared to age-matched WT or littermate controls. Data compared CBCs from 10 WT and 11 CD2-icre ABCB7 cKO mice. Statistical analysis was performed using Student’s t test. **p ⁇ 0.01, *** p ⁇ 0.001.
  • Figure 8 Analysis of myeloid populations in the spleen from CD2-icre ABCB7 cKO mice as compared to age-matched WT or littermate controls.
  • Figure 9 Similar frequencies and numbers of LSK cells in the bone marrow from older/sick CD2-icre ABCB7 cKO mice as compared to age-matched WT or littermate controls.
  • Figure 10 Analysis of splenic stress erythropoiesis using CD71 and Teri 19 in mbl- cre ABCB7 cKO mice as compared to age-matched WT or littermate controls.
  • Figure 11 Analysis of myeloid populations in the spleen from mb 1 -ere ABCB7 cKO mice as compared to age-matched WT or littermate controls.
  • Figure 12 Upregulation of CD80 on bone marrow macrophages (CD1 lb + Ly6G’ F4/80 + ) from older/sick CD2-icre ABCB7 cKO mice as compared to age-matched ABCB7 11 fl littermate controls.
  • FIG. 13 Expression of a LSL-Tomato (TMT) reporter in splenic B cells (top) macrophages (middle) or neutrophils (bottom) in LSL-Tomato CD2-icre ABCB7 cKO mice (right) as compared to LSL-Tomato CD2-icre (ABCB7 WT) mice (left).
  • TMT LSL-Tomato
  • Figure 14 Analysis of myeloid populations in the spleen from CD2-icre ABCB7 cKO mice and CD2-icre ABCB7 cKO/C/EBPa cKO as compared to age-matched ABCB7 floxed controls.
  • Figures 15A-15B ABCB7 was required for erythropoiesis.
  • Figure 15 A Example of wild-type littermate and ErGFP-cre ABCB7 cKO embryos.
  • Figure 15B Flow cytometry analysis of erythropoiesis at el0.5. Left panel shows gating strategy for R1-R5 gates. ErGFP- cre ABCB7 cKO embryos had a block in erythropoiesis at the R3 CD71 high Teri 19 + stage.
  • Figure 16 ABCB7-deficient pro-B cells had increased PARP1 expression. Analysis of PARP1 expression in Fr C/C' in pro-B cells from WT and mb 1 -ere ABCB7 cKO mice. Representative FACS analysis is shown at left and quantified at right.
  • FIG 17 Induction of myc-tagged ABCB7 by doxycycline (dox).
  • Multipotent progenitors (MPPs) from rtTA ABCB7myc mice were expanded in culture, and treated with dox for 0, 1 or 2 days.
  • Expression of myc-tagged ABCB7 was examined by Western blot with actin serving as a loading control.
  • This document provides methods and materials for treating myeloid disorders (e.g., SF3B1 -associated myeloid disorders). For example, this document provides methods and materials for using one or more inhibitors of early lymphopoiesis to treat a mammal (e g., a human) having a myeloid disorder (e.g., a SF3B1 -associated myeloid disorder). For example, one or more inhibitors of early lymphopoiesis can be administered to a mammal (e.g., a human) having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) to treat the mammal.
  • a mammal e.g., a human
  • myeloid disorder e.g., SF3B1 -associated myeloid disorder
  • the methods do not include administering any intravenous immunoglobulin (IVIG) to the mammal.
  • IVIG intravenous immunoglobulin
  • a mammal e.g., a human
  • a myeloid disorder e.g., SF3B1-associated myeloid disorder
  • the mammal can have any type of myeloid disorder.
  • a myeloid disorder can be a SF3B1 -associated myeloid disorder.
  • a myeloid disorder can be a MDS.
  • a myeloid disorder can be a MPN.
  • a myeloid disorder can include cell-extrinsic emergency myelopoiesis.
  • the SF3B1 -associated myeloid disorder can be any appropriate SF3B1 -associated myeloid disorder.
  • a SF3B1 -associated myeloid disorder can be a myeloid disorder that includes the expression of a modified SF3B1 polypeptide (e.g., a SF3B1 polypeptide having a K700E modification) by hematopoietic cells.
  • a SF3B1 -associated myeloid disorder can be a myeloid disorder that includes a reduced expression level of an ATP-binding cassette sub-family B member 7 (ABCB7) polypeptide by hematopoietic cells.
  • the term “reduced level” as used herein with respect to a level of an ABCB7 polypeptide refers to any level that is lower than a reference level of the ABCB7 polypeptide.
  • reference level as used herein with respect to a level of an ABCB7 polypeptide refers to the level of the ABCB7 polypeptide typically observed in a mammal that does not have a SF3B1 -associated myeloid disorder (e.g., a healthy mammal).
  • a SF3B1 -associated myeloid disorder can be a myeloid disorder that includes expression of a modified SF3B1 polypeptide (e.g., a SF3B1 polypeptide having a K700E modification) by hematopoietic cells, which can generate aberrant splicing of an ABCB7 messenger RNA (mRNA; e.g., between exons 8 and 9) leading to nonsense-mediated decay of the ABCB7 mRNA and a reduced level of expression of an ABCB7 polypeptide by hematopoietic cells.
  • mRNA ABCB7 messenger RNA
  • a SF3B1 -associated myeloid disorder can be as described elsewhere (see, e.g., Mangaonkar et al., Haematol ogica, 107: 1189-1192 (2022); Venable et al., Am. J. Clin. Pathol., 156:679-690 (2021); Patnaik et al., Am. J. HematoL, 96:379-394 (2021); Patnaik et al., Am. J. HematoL, 92:297-310 (2017); and Wudhikarn et al., Blood Adv., 4:5716-5721 (2020)).
  • any type of mammal having a myeloid disorder can be treated as described herein.
  • mammals that can be treated with one or more inhibitors of early lymphopoiesis as described herein include, without limitation, humans, non-human primates (e.g., monkeys), dogs, cats, horses, cows, pigs, sheep, rabbits, mice, and rats.
  • a human having a myeloid disorder e.g., SF3B1 -associated myeloid disorder
  • the methods provided herein can include identifying a mammal (e.g., a human) as having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder).
  • a mammal e.g., a human
  • a myeloid disorder e.g., SF3B1 -associated myeloid disorder
  • Any appropriate method can be used to identify a mammal as having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder).
  • analysis of complete blood counts, blood smears, and/or bone marrow aspirates can be used to identify a human or other mammal as having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder).
  • a mammal having a myeloid disorder can be administered or instructed to self-administer one or more (e.g., one, two, three, four, or more) inhibitors of early lymphopoiesis described herein.
  • an “inhibitor of early lymphopoiesis” can be any agent that can target developing B cells (e.g., pro-B cells such as early pro-B cells and late pro-B cells) without targeting peripheral B cells.
  • an inhibitor of early lymphopoiesis can target (e.g., target and destroy) one or more B cell progenitor cells.
  • an inhibitor of early lymphopoiesis can target (e.g., target and destroy) a common lymphoid progenitor (CLP) cell.
  • an inhibitor of early lymphopoiesis can target (e.g., target and destroy) a pre-pro-B (PPB) cell.
  • an inhibitor of early lymphopoiesis can reduce or eliminate the transition of one or more B cell progenitor cells into B cells.
  • an inhibitor of early lymphopoiesis can reduce or eliminate the transition of a multipotent progenitor (MPP) cell into a B cell.
  • MPP multipotent progenitor
  • an inhibitor of early lymphopoiesis can reduce or eliminate the transition of a CLP cell into a B cell.
  • an inhibitor of early lymphopoiesis can reduce or eliminate the transition of a PPB cell into a B cell.
  • an inhibitor of early lymphopoiesis can be an inhibitor of a fms like tyrosine kinase 3 (FLT3) polypeptide.
  • An inhibitor of a FLT3 polypeptide can be an inhibitor of FLT3 polypeptide activity (e.g., anti-FLT3 antibodies such as neutralizing anti-FLT3 antibodies and small molecules that target a FLT3 polypeptide) or an inhibitor of FLT3 polypeptide expression (e.g., nucleic acid molecules designed to induce RNA interference (RNAi) of FLT3 polypeptide expression such as antisense oligonucleotides (ASOs), siRNA molecules, and shRNA molecules).
  • RNAi RNA interference
  • an inhibitor of a FLT3 polypeptide can be in the form of a bispecific antibody. In some cases, an inhibitor of a FLT3 polypeptide can be in the form of a proteolysis targeting chimera (PROTACTM). In some cases, an inhibitor of a FLT3 polypeptide can be in the form of a trispecific T cell activating construct (TriTACTM). In some cases, an inhibitor of a FLT3 polypeptide can be in the form of an antibody-drug conjugate (ADC). Examples of inhibitors of a FLT3 polypeptide that can be used to treat a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) as described herein can be as shown in Table 1.
  • a myeloid disorder e.g., SF3B1 -associated myeloid disorder
  • Additional inhibitors of a FLT3 polypeptide can be designed based on any appropriate nucleic acid (e g., a mRNA) encoding a FLT3 polypeptide sequence.
  • nucleic acids encoding a FLT3 polypeptide sequence include, without limitation, those set forth in National Center for Biotechnology Information (NCBI) accession no. NM 004119 (version NM_004119.3).
  • the methods provided herein can include administering one or more (e.g., one, two, three, four, or more) agents that can target (e.g., target and destroy) FLT3 + cells to a mammal (e.g., a human) having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) to treat the mammal.
  • a mammal e.g., a human
  • a myeloid disorder e.g., SF3B1 -associated myeloid disorder
  • T cells expressing e.g., designed to express) a chimeric antigen receptor (CAR) that can target a FLT3 polypeptide (FLT3-CAR T cells), such as HEMO- CAR-T cells (see, e.g., hemogenyx.com), can be administered to a mammal (e.g., a human) having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) to target (e.g., target and destroy) FLT3 + cells within the mammal.
  • a mammal e.g., a human
  • a myeloid disorder e.g., SF3B1 -associated myeloid disorder
  • target e.g., target and destroy
  • an inhibitor of early lymphopoiesis can be an inhibitor of an interleukin 7 (IL-7) polypeptide.
  • An inhibitor of an IL-7 polypeptide can be an inhibitor of IL-7 polypeptide activity (e g., anti-IL-7 antibodies such as neutralizing anti-IL-7 antibodies and small molecules that target an IL-7 polypeptide) or an inhibitor of IL-7 polypeptide expression (e.g., nucleic acid molecules designed to induce RNAi of IL-7 polypeptide expression such as ASOs, siRNA molecules, and shRNA molecules).
  • an inhibitor of an IL-7 polypeptide can be in the form of a bispecific antibody (e.g., a bispecific antibody that can target and bind both an IL-7 polypeptide and a programmed cell death protein 1 (PD-1) polypeptide such as a BiCKI®-IL-7 antibody).
  • an inhibitor of an IL-7 polypeptide can be in the form of a PROTACTM.
  • an inhibitor of an IL- 7 polypeptide can be in the form of a TriTACTM.
  • an inhibitor of an IL-7 polypeptide can be in the form of an ADC. Examples of inhibitors of an IL-7 polypeptide that can be used to treat a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) as described herein can be as shown in Table 2.
  • Additional inhibitors of an IL-7 polypeptide can be designed based on any appropriate nucleic acid (e.g., a mRNA) encoding an IL-7 polypeptide sequence.
  • nucleic acids encoding an IL-7 polypeptide sequence include, without limitation, those set forth in NCBI accession no. NM_001410734 (version NM_001410734. 1).
  • an inhibitor of an IL-7 receptor IL-7R
  • an IL-7 receptor can be used in place of or in addition to an inhibitor of an IL-7 polypeptide to treat a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) as described herein.
  • myeloid disorder e.g., SF3B1 -associated myeloid disorder
  • inhibitors of an IL-7 receptor include, without limitation, GIFT-7, ASP-9801, BNT-152, ZB-168, ADX-914, bempikibart, lusvertikimab, KG-002, and B-12.
  • the methods provided herein can include administering one or more (e.g., one, two, three, four, or more) agents that can target (e.g., target and destroy) IL-7 + cells to a mammal (e g., a human) having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) to treat the mammal.
  • a mammal e.g., a human
  • a myeloid disorder e.g., SF3B1 -associated myeloid disorder
  • T cells expressing (e.g., designed to express) a CAR that can target a melanoma-associated antigen 4 (MAEG-4) polypeptide and expressing an IL-7 polypeptide can be administered to a mammal (e.g., a human) having a myeloid disorder (e.g., SF3B1- associated myeloid disorder) to target (e.g., target and destroy) IL-7 + cells within the mammal.
  • a mammal e.g., a human
  • a myeloid disorder e.g., SF3B1- associated myeloid disorder
  • target e.g., target and destroy
  • lymphocytes e.g., tumor-infiltrating lymphocytes
  • a mammal e.g., a human
  • a myeloid disorder e.g., SF3B1 -associated myeloid disorder
  • target e.g., target and destroy
  • one or more agents designed to induce an immune response against an IL-7 polypeptide can be administered to a mammal (e.g., a human) having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) to target (e.g., target and destroy) IL-7 + cells within the mammal.
  • a mammal e.g., a human
  • a myeloid disorder e.g., SF3B1 -associated myeloid disorder
  • target e.g., target and destroy
  • the methods provided herein can include administering one or more (e.g., one, two, three, four, or more) agents that can target (e.g., target and destroy) IL-7R + cells (e.g., IL-7Ra cells) to a mammal (e.g., a human) having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) to treat the mammal.
  • a mammal e.g., a human
  • myeloid disorder e.g., SF3B1 -associated myeloid disorder
  • T cells expressing (e.g., designed to express) a CAR that can target a CD19 polypeptide and expressing an IL-7 polypeptide can be administered to a mammal (e.g., a human) having a myeloid disorder (e.g., SF3Bl-associated myeloid disorder) to target (e.g., target and destroy) IL-7Ra + cells within the mammal.
  • a mammal e.g., a human
  • a myeloid disorder e.g., SF3Bl-associated myeloid disorder
  • target e.g., target and destroy
  • an inhibitor of early lymphopoiesis can be as described elsewhere (see, e.g., Medina, Int. J. Mol. Sci., 23(13):7289 (2022); Medina et al., Curr. Opin. Hematol., 12(3):203-9 (2005); Sun et al., Biomed. Pharmacother ., 169: 115905 (2023); Wang et al., Future Med. Chem., 15( 1): 57-71 (2023); Zhang et al., Bioorg. Med. Chem. Lett., 30(22): 127532 (2020); Yuan et al., Eur. J. Med.
  • One or more inhibitors of early lymphopoiesis described herein can be formulated into a composition (e.g., a pharmaceutically acceptable composition) for administration to a mammal having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder).
  • a therapeutically effective amount of one or more inhibitors of early lymphopoiesis described herein can be formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • a pharmaceutical composition can be formulated for administration in solid or liquid form including, without limitation, sterile solutions, suspensions, sustained-release formulations, tablets, capsules, pills, powders, and granules.
  • a composition including one or more inhibitors of early lymphopoiesis described herein can be administered locally or systemically.
  • a composition containing one or more inhibitors of early lymphopoiesis described herein can be designed for oral or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal).
  • a composition containing one or more inhibitors of early lymphopoiesis described herein can be administered systemically by an oral administration to or inhalation by a mammal (e.g., a human).
  • a composition containing one or more inhibitors of early lymphopoiesis described herein can be in the form of a pill, tablet, or capsule.
  • one or more (e.g., one, two, three, four, or more) inhibitors of early lymphopoiesis can be used to reduce the severity of one or more symptoms of a myeloid disorder (e.g., SF3B1 -associated myeloid disorder).
  • a myeloid disorder e.g., SF3B1 -associated myeloid disorder
  • one or more inhibitors of early lymphopoiesis can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having a myeloid disorder such as a SF3B1 -associated myeloid disorder) to reduce the severity of one or more symptoms of the myeloid disorder.
  • myeloid disorders examples include, without limitation, fatigue, shortness of breath, pallor, easy or unusual bruising or bleeding, pinpoint-sized red spots just beneath the skin that are caused by bleeding, frequent infections, weakness, lightheadedness, and fever.
  • the methods and materials described herein can be effective to reduce the severity of one or more symptoms of a myeloid disorder (e.g., SF3B1- associated myeloid disorder) in a mammal having a myeloid disorder (e.g., SF3Bl-associated myeloid disorder) by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.
  • one or more (e.g., one, two, three, four, or more) inhibitors of early lymphopoiesis can be used to reduce myelopoiesis.
  • one or more inhibitors of early lymphopoiesis can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having a myeloid disorder such as a SF3B1 -associated myeloid disorder) to reduce myelopoiesis within the mammal.
  • the methods and materials described herein can be effective to reduce myelopoiesis in a mammal having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.
  • a myeloid disorder e.g., SF3B1 -associated myeloid disorder
  • the methods and materials described herein can be effective to reduce myelopoiesis in a mammal having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) such that a blood sample obtained from the mammal after being administered one or more inhibitors of early lymphopoiesis as described herein includes a red blood cell (RBC) count of at least 3.9 million cells per microliter (pL) of blood.
  • a myeloid disorder e.g., SF3B1 -associated myeloid disorder
  • the methods and materials described herein can be effective to reduce myelopoiesis in a mammal having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) such that a blood sample obtained from the mammal after being administered one or more inhibitors of early lymphopoiesis as described herein includes a RBC count of from about 3.9 million cells to about 5.6 million cells per pL of blood (e.g., from about 3.9 million cells to about 5 million cells, from about 3.9 million cells to about 4.5 million cells, from about 3.9 million cells to about 4.2 million cells, from about 4 million cells to about 5.6 million cells, from about 4.2 million cells to about 5.6 million cells, from about 4.5 million cells to about 5.6 million cells, from about 4.8 million cells to about 5.6 million cells, from about 5.1 million cells to about 5.6 million cells, from about 4.1 million cells to about 5.2 million cells, from about 4.4 million cells to about 4.8 million cells, from about 4 million cells to about 4.5 million cells
  • one or more inhibitors of early lymphopoiesis described herein can be used as the sole active agent to treat a mammal (e.g., a human) having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder).
  • a mammal e.g., a human
  • myeloid disorder e.g., SF3B1 -associated myeloid disorder
  • one or more inhibitors of early lymphopoiesis described herein can be administered to a mammal (e.g., a human) having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) together with one or more (e.g., one, two, three, four, or more) additional agents/therapies used to treat a myeloid disorder (or to treat one or more symptoms of a myeloid disorder).
  • a mammal e.g., a human
  • a myeloid disorder e.g., SF3B1 -associated myeloid disorder
  • additional agents/therapies used to treat a myeloid disorder (or to treat one or more symptoms of a myeloid disorder).
  • agents that can be used to treat a myeloid disorder include, without limitation, azacytidine (e.g., ONUREG® and VID AZA®), decitabine, erythropoietin (EPO), lenalidomide, and any combinations thereof.
  • azacytidine e.g., ONUREG® and VID AZA®
  • decitabine e.g., erythropoietin (EPO), lenalidomide
  • EPO erythropoietin
  • lenalidomide e.g., lenalidomide
  • the one or more additional agents can be administered at the same time (e g., in a single composition containing one or more inhibitors of early lymphopoiesis described herein and the one or more additional agents) or independently.
  • one or more inhibitors of early lymphopoiesis described herein can be administered first, and the one or more additional agents administered second, or vice versa.
  • therapies that can be used to treat a myeloid disorder (or to treat one or more symptoms of a myeloid disorder) include, without limitation, blood transfusions and bone marrow transplants.
  • the one or more additional therapies can be performed at the same time or independently of the administration of one or more inhibitors of early lymphopoiesis described herein.
  • one or more inhibitors of early lymphopoiesis described herein can be administered before, during, or after the one or more additional therapies are performed.
  • Example 1 SF3B1 -associated myelodysplasia is and decreased expression of ABCB7 in B- lineage precursor cells
  • ABCB7 is required for B cell development beyond the pro-B cell stage
  • ABCB7-deficient pro-B cells had increased expression of phospho-H2AX, which accumulates at sites of DNA damage ( Figures 4A-4B). This increase was primarily found in proliferating pro-B cells, as demonstrated by EdU incorporation ( Figures 4A-4B). Both the percent and rate of EdU incorporation was also decreased in ABCB7-deficient pro-B cells, indicating that there appears to be a defect in DNA replication ( Figures 4C-4D). These data suggest that DNA- damaged ABCB7-deficient B cells can produce a danger signal or inflammation in the bone marrow leading to cell-extrinsic effects on hematopoiesis.
  • mice initiated splenic stress erythropoiesis (Figure 6).
  • the spleen was enlarged, with a significant increase in both monocytes (Ly6C hl Ly6G‘) and neutrophils (LyG6 + ).
  • Bone marrow macrophages from CD2-icre ABCB7 cKO mice had increased expression of CD80, indicative of activation ( Figure 12).
  • CD2-icre ABCB7 cKO mice were interbred with a lox-stop-lox (LSL) Tomato reporter mouse such that all cells that expressed ere, or that had a progenitor that expressed ere, expressed the Tomato reporter.
  • LSL lox-stop-lox
  • CD19 + B cells were efficiently labelled with the reporter, monocytes, macrophages, or neutrophils in CD2-icre ABCB7 cKO mice primarily lacked reporter expression (Figure 13). These results demonstrated that the effects on myelopoiesis were cell-extrinsic and not mediated by cre-deletion. To confirm this further, CD2-icre ABCB7 cKO/C/EBPa cKO mice were generated. C/EBPa is required for macrophage and neutrophil development, and CD2-icre deletion was restricted to lymphocytes, such that if there is cre-deletion occurring in myeloid precursors, then myelopoiesis is disrupted in CD2-icre ABCB7 cKO/C/EBPa cKO mice.
  • ABCB7 floxed mice were interbred with ErGFP-cre mice in which GFP -tagged ere was knocked into the erythropoietin receptor locus, restricting expression of ere exclusively to the erythroid lineage and no other hematopoietic lineage.
  • the resulting litters lacked any ErGFP-cre ABCB7 cKO pups at weaning or at birth, indicating that the loss of ABCB7 in the erythroid lineage results in embryonic lethality.
  • R1 (CD71 med Terl 19-) contains early erythroid progenitors and proerythroblasts
  • R2 CD71 hlsh Terl l9‘ /low ) contains pro-erythroblasts and early basophilic erythroblasts
  • R3 (CD71 hlgh Terl 19 + ) contains basophilic erythroblasts
  • R4 (CD71 med Terl 19 + ) contains chromatophilic and orthochromatophilic erythroblasts
  • R5 (CD71 low Terl l9 + ) contains late orthochromatophilic erythroblasts.
  • ABCB7-myc A dox-regulated myc-tagged allele of ABCB7 (hereafter called ABCB7-myc) was generated.
  • a myc-tagged ABCB7 cDNA was inserted downstream of a minimal promoter regulated by Tet-responsive elements engineered upstream.
  • This plasmid also contained FRT sites for homologous recombination in engineered ES cells for insertion into the Col Al locus. Targeted ES cells were generated, and germline transmission has been achieved.
  • rtTA ABCB7myc mice were generated. Hematopoietic progenitors from rtTA ABCB7myc mice were expanded in culture and treated with dox or left untreated. As shown in Figure 17, dox treatment led to expression of myc- tagged ABCB7, confirming that a mouse with a dox-regulated allele of ABCB7 was generated.
  • a human identified as having a SF3B1 -associated myeloid disorder is administered one or more inhibitors of early lymphopoiesis (e.g., midostaurin, gilteritinib, quizartinib, sorafenib, sunitinib, lestaurtinib, tandutinib, crenolanib, AIU2008, ALLO-819, BGS-2456, BMF-500, CCT245718, CDDD11-8, CHMFL-FLT3-213, CHMFL-FLT3-335, clifutinib besylate, CLN-049, CRBN(FLT3)-8, crenolanib besylate, creserol, CTS-2016, cytarabine/daunorubicin, D-64406, D-65476, danatinib, dapolsertib, E2082-0047, E-6201, EC-70124, EP-0042
  • the administered inhibitor(s) can reduce the severity of one or more symptoms of a SF3B1 -associated myeloid disorder (e.g., fatigue, shortness of breath, pallor, easy or unusual bruising or bleeding, pinpoint-sized red spots just beneath the skin that are caused by bleeding, frequent infections, weakness, lightheadedness, and/or fever).
  • a SF3B1 -associated myeloid disorder e.g., fatigue, shortness of breath, pallor, easy or unusual bruising or bleeding, pinpoint-sized red spots just beneath the skin that are caused by bleeding, frequent infections, weakness, lightheadedness, and/or fever).

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Abstract

This document relates to methods and materials for treating myeloid disorders in a mammal (e.g., a human). For example, methods and materials for using one or more inhibitors of early lymphopoiesis to treat a mammal having a myeloid disorder (e.g., a SF3B1-associated myeloid disorder) are provided.

Description

TREATING MYELOID DISORDERS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Patent Application Serial No. 63/526,618, filed on July 13, 2023. The disclosure of the prior application is considered part of, and is incorporated by reference in, the disclosure of this application.
TECHNICAL FIELD
This document relates to methods and materials for treating myeloid disorders (e.g., splicing factor 3B subunit 1 (SF3Bl)-associated myeloid disorders). For example, this document provides methods and materials for using one or more inhibitors of early lymphopoiesis to treat a mammal (e.g., a human) having a myeloid disorder (e.g., a SF3B1- associated myeloid disorder).
BACKGROUND
Hematopoiesis is tightly regulated to maintain production of terminally differentiated hematopoietic lineages required for survival. As individuals age, mutations that arise within hematopoietic progenitors can lead to dysregulated hematopoiesis. Dysregulation of myelopoiesis can be either cell-intrinsic or cell-extrinsic. Cell-intrinsic mutations typically result in myelodysplastic syndromes (MDSs) or myeloproliferative disorders (MPNs), while cell-extrinsic systemic inflammation can promote emergency myelopoiesis. However, the cause of the enhanced myelopoiesis is not always clear, and these two mechanisms are not necessarily mutually exclusive. Further, upon additional somatic mutations, both MDSs and MPNs have the potential to progress into acute myeloid leukemia (AML).
A common mutation in several heterogenous myeloid disorders is in the RNA splicing protein SF3B1 (Mangaonkar et al., Haematologica, 107: 1189-1192 (2022); and Venable et al., Am. J. Clin. Pathol., 156:679-690 (2021)). SF3B1 mutations are found in many subtypes of myeloid disorders (Patnaik et al., Am. J. HematoL, 96:379-394 (2021); Patnaik et al., Am. J. HematoL, 92:297-310 (2017); and Wudhikarn et al., Blood Adv., 4:5716-5721 (2020)), and the heterogeneity observed between different hematological diseases with SF3B1 mutations is likely due to the presence of additional mutations (Venable et al., Am. J. Clin. Pathol., 156:679-690 (2021)).
SUMMARY
This document provides methods and materials for treating myeloid disorders (e.g., SF3B1 -associated myeloid disorders). For example, this document provides methods and materials for administering one or more inhibitors of early lymphopoiesis to a mammal (e.g., a human) having a myeloid disorder (e.g., a SF3B1 -associated myeloid disorder) to treat the mammal. As described herein, targeting earlier B-lineage precursor cells can restore normal myelopoiesis and erythropoiesis, and can be used to treat myeloid disorders (e.g., SF3B1- mutated myeloid disorders). For example, one or more inhibitors of early lymphopoiesis can be used treat a mammal (e.g., a human) having a myeloid disorder (e.g., a SF3B1 -associated myeloid disorder). In some cases, one or more inhibitors of early lymphopoiesis can be administered to a mammal (e.g., a human) having a myeloid disorder (e.g., a SF3B1- associated myeloid disorder) to treat the mammal. Having the ability to treat myeloid disorders as described herein (e.g., by administering one or more inhibitors of early lymphopoiesis) provides a unique and unrealized opportunity to treat the disease rather than just the symptoms.
In general, one aspect of this document features methods for treating a SF3B1- associated myeloid disorder. The methods can include, or consist essentially of, administering an inhibitor of early lymphopoiesis to a mammal identified as having a SF3B1- associated myeloid disorder. The mammal can be a human. The hematopoietic cells of the mammal can express a reduced level of an AFP -binding cassette sub-family B member 7 (ABCB7) polypeptide as compared to the level of expression of said ABCB7 polypeptide by hematopoietic cells of a healthy mammal not having said SF3B1 -associated myeloid disorder. The SF3B1 -associated myeloid disorder can be a SF3B1 -associated myelodysplastic syndrome. The SF3B1 -associated myeloid disorder can be a SF3B1- associated myeloproliferative disorder. The inhibitor of early lymphopoiesis can be midostaurin, gilteritinib, quizartinib, sorafenib, sunitinib, lestaurtinib, tandutinib, crenolanib, AIU2008, ALLO-819, BGS-2456, BMF-500, CCT245718, CDDD11-8, CHMFL-FLT3-213, CHMFL-FLT3-335, clifutinib besylate, CLN-049, CRBN(FLT3)-8, crenolanib besylate, creserol, CTS-2016, cytarabine/daunorubicin, D-64406, D-65476, danatinib, dapolsertib, E2082-0047, E-6201, EC-70124, EP-0042, ETH-155036, gilteritinib fumarate, H-104, Jil l 8, HD- 10019, HEC-73543, HP 1328, HPB-092, HSD1169, HSK-205, HSN-431, HYML- 122, JH-IX-179, K783-0308, KRX-107, KWB-201, LGR-3922, LNX-231, lomonitinib, LT- 171-861, LT-540-717, LT-850-166, luxeptinib, LWY713, MIC135, MRX-2843, MZH29, NCGC-1481, nefextinib, ningetinib tosylate, nintedanib esylate, ON-150030, pacritinib, PHI- 101, PLD-102, PLM-102, pluripotin, quizartinib hydrochloride, RF-1302, ruserontinib, SENTI-202, SKLB-677, SLX 0953, sorafenib tosylate, STI-8591, T-1301, TLX83, TP-P1, TSD204, TSN-084, TT-00973, tuspetinib, XY0206, GSK2618960, ADX-914, PF-06342674, GIFT-7, ASP-9801, BNT-152, GSK-3888130B, KG-002, FT-873, HCW-9206, GIFT-7, ASP-9801, BNT-152, ZB-168, ADX-914, bempikibart, lusvertikimab, KG-002, or B-12.
In another aspect, this document features methods for treating a mammal having a SF3B1 -associated myeloid disorder. The methods can include, or consist essentially of, administering an inhibitor of early lymphopoiesis to a mammal having a SF3B1 -associated myeloid disorder. The mammal can be a human. The hematopoietic cells of the mammal can express a reduced level of an ATP-binding cassette sub-family B member 7 (ABCB7) polypeptide as compared to the level of expression of said ABCB7 polypeptide by hematopoietic cells of a healthy mammal not having said SF3B1 -associated myeloid disorder. The SF3B1 -associated myeloid disorder can be a SF3B1 -associated myelodysplastic syndrome. The SF3B1 -associated myeloid disorder can be a SF3B1- associated myeloproliferative disorder. The inhibitor of early lymphopoiesis can be midostaurin, gilteritinib, quizartinib, sorafenib, sunitinib, lestaurtinib, tandutinib, crenolanib, AIU2008, ALLO-819, BGS-2456, BMF-500, CCT245718, CDDD11-8, CHMFL-FLT3-213, CHMFL-FLT3-335, clifutinib besylate, CLN-049, CRBN(FLT3)-8, crenolanib besylate, creserol, CTS-2016, cytarabine/daunorubicin, D-64406, D-65476, danatinib, dapolsertib, E2082-0047, E-6201, EC-70124, EP-0042, ETH-155036, gilteritinib fumarate, H-104, H- 118, HD- 10019, HEC-73543, HP 1328, HPB-092, HSD 1169, HSK-205, HSN-431 , HYML- 122, JH-IX-179, K783-0308, KRX-107, KWB-201, LGR-3922, LNX-231, lomonitinib, LT- 171-861, LT-540-717, LT-850-166, luxeptinib, LWY713, MIC135, MRX-2843, MZH29, NCGC-1481, nefextinib, ningetinib tosylate, nintedanib esylate, ON- 150030, pacritinib, PHI- 101, PLD-102, PLM-102, pluripotin, quizartinib hydrochloride, RF-1302, ruserontinib, SENTI-202, SKLB-677, SLX 0953, sorafenib tosylate, STI-8591, T-1301, TLX83, TP-P1, TSD204, TSN-084, TT-00973, tuspetinib, XY0206, GSK2618960, ADX-914, PF-06342674, GIFT-7, ASP-9801, BNT-152, GSK-3888130B, KG-002, FT-873, HCW-9206, GIFT-7, ASP-9801, BNT-152, ZB-168, ADX-914, bempikibart, lusvertikimab, KG-002, or B-12.
In another aspect, this document features uses of a composition comprising an inhibitor of early lymphopoiesis to treat a SF3B1 -associated myeloid disorder. The SF3B1- associated myeloid disorder can be a SF3B1 -associated myelodysplastic syndrome. The SF3B1 -associated myeloid disorder can be a SF3B1 -associated myeloproliferative disorder. The inhibitor of early lymphopoiesis can be midostaurin, gilteritinib, quizartinib, sorafenib, sunitinib, lestaurtinib, tandutinib, crenolanib, AIU2008, ALLO-819, BGS-2456, BMF-500, CCT245718, CDDD11-8, CHMFL-FLT3-213, CHMFL-FLT3-335, clifutinib besylate, CLN- 049, CRBN(FLT3)-8, crenolanib besylate, creserol, CTS-2016, cytarabine/daunorubicin, D- 64406, D-65476, danatinib, dapolsertib, E2082-0047, E-6201, EC-70124, EP-0042, ETH- 155036, gilteritinib fumarate, H-104, H-118, HD-10019, HEC-73543, HP1328, HPB-092, HSD1169, HSK-205, HSN-431, HYML-122, JH-IX-179, K783-0308, KRX-107, KWB-201, LGR-3922, LNX-231, lomonitinib, LT-171-861, LT-540-717, LT-850-166, luxeptinib, LWY713, MIC135, MRX-2843, MZH29, NCGC-1481, nefextinib, ningetinib tosylate, nintedanib esylate, ON-150030, pacritinib, PHI-101, PLD-102, PLM-102, pluripotin, quizartinib hydrochloride, RF-1302, ruserontinib, SENTI-202, SKLB-677, SLX 0953, sorafenib tosylate, STI-8591, T-1301, TLX83, TP-P1, TSD204, TSN-084, TT-00973, tuspetinib, XY0206, GSK2618960, ADX-914, PF-06342674, GIFT- 7, ASP-9801, BNT-152, GSK-3888130B, KG-002, FT-873, HCW-9206, GIFT-7, ASP-9801, BNT-152, ZB-168, ADX-914, bempikibart, lusvertikimab, KG-002, or B-12.
In another aspect, this document features inhibitors of early lymphopoiesis for use in the preparation of a medicament to treat a SF3B1 -associated myeloid disorder. The SF3B1- associated myeloid disorder can be a SF3B1 -associated myelodysplastic syndrome. The SF3B1 -associated myeloid disorder can be a SF3B1 -associated myeloproliferative disorder. The inhibitor of early lymphopoiesis can be midostaurin, gilteritinib, quizartinib, sorafenib, sunitinib, lestaurtinib, tandutinib, crenolanib, AIU2008, ALLO-819, BGS-2456, BMF-500, CCT245718, CDDD11-8, CHMFL-FLT3-213, CHMFL-FLT3-335, clifutinib besylate, CLN- 049, CRBN(FLT3)-8, crenolanib besylate, creserol, CTS-2016, cytarabine/daunorubicin, D- 64406, D-65476, danatinib, dapolsertib, E2082-0047, E-6201, EC-70124, EP-0042, ETH- 155036, gilteritinib fumarate, H-104, H-118, HD-10019, HEC-73543, HP1328, HPB-092, HSD1169, HSK-205, HSN-431, HYML-122, JH-IX-179, K783-0308, KRX-107, KWB-201, LGR-3922, LNX-231, lomonitinib, LT-171-861, LT-540-717, LT-850-166, luxeptinib, LWY713, MIC135, MRX-2843, MZH29, NCGC-1481, nefextinib, ningetinib tosylate, nintedanib esylate, ON-150030, pacritinib, PHI-101, PLD-102, PLM-102, pluripotin, quizartinib hydrochloride, RF-1302, ruserontinib, SENTI-202, SKLB-677, SLX 0953, sorafenib tosylate, STI-8591, T-1301, TLX83, TP-P1, TSD204, TSN-084, TT-00973, tuspetinib, XY0206, GSK2618960, ADX-914, PF-06342674, GIFT-7, ASP-9801, BNT-152, GSK-3888130B, KG-002, FT-873, HCW-9206, GIFT-7, ASP-9801, BNT-152, ZB-168, ADX-914, bempikibart, lusvertikimab, KG-002, or B-12.
In another aspect, this document features inhibitors of early lymphopoiesis for use in the treatment of a SF3B1 -associated myeloid disorder. The SF3B1 -associated myeloid disorder can be a SF3B1 -associated myelodysplastic syndrome. The SF3B1 -associated myeloid disorder can be a SF3B1 -associated myeloproliferative disorder. The inhibitor of early lymphopoiesis can be midostaurin, gilteritinib, quizartinib, sorafenib, sunitinib, lestaurtinib, tandutinib, crenolanib, AIU2008, ALLO-819, BGS-2456, BMF-500, CCT245718, CDDD11-8, CHMFL-FLT3-213, CHMFL-FLT3-335, clifutinib besylate, CLN- 049, CRBN(FLT3)-8, crenolanib besylate, creserol, CTS-2016, cytarabine/daunorubicin, D- 64406, D-65476, danatinib, dapolsertib, E2082-0047, E-6201, EC-70124, EP-0042, ETH- 155036, gilteritinib fumarate, H-104, H-118, HD-10019, HEC-73543, HP1328, HPB-092, HSD1169, HSK-205, HSN-431, HYML-122, JH-IX-179, K783-0308, KRX-107, KWB-201, LGR-3922, LNX-231, lomonitinib, LT-171-861, LT-540-717, LT-850-166, luxeptinib, LWY713, MIC135, MRX-2843, MZH29, NCGC-1481, nefextinib, ningetinib tosylate, nintedanib esylate, ON-150030, pacritinib, PHI-101, PLD-102, PLM-102, pluripotin, quizartinib hydrochloride, RF-1302, ruserontinib, SENTI-202, SKLB-677, SLX 0953, sorafenib tosylate, STI-8591, T-1301, TLX83, TP-P1, TSD204, TSN-084, TT-00973, tuspetinib, XY0206, GSK2618960, ADX-914, PF-06342674, GIFT-7, ASP-9801, BNT-152, GSK-3888130B, KG-002, FT-873, HCW-9206, GIFT-7, ASP-9801, BNT-152, ZB-168, ADX-914, bempikibart, lusvertikimab, KG-002, or B-12. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 : A schematic showing that depletion of ABCB7 in the B-cell lineage leads to cell-extrinsic emergency myelopoiesis.
Figures 2A-2D: B cell development was blocked at the pro-B cell stage in mbl-cre ABCB7 cKO mice. Figure 2A) A representative FACS analysis of the Hardy fractions between WT, mbl-cre ABCB7 cKO, and CD23-cre ABCB7 cKO mice in the bone marrow. Figure 2B) Representative data of splenic B cell populations from WT, mbl-cre ABCB7 cKO, and CD23-cre ABCB7 cKO mice. Figures 2C-2D) Quantitation of Hardy Fractions (Figure 2C) and splenic B cells (Figure 2D) from WT, mbl-cre ABCB7 cKO, and CD23-cre ABCB7 cKO mice. Data are representative of at least 5 mice per group. *p<0.05, **p<0.01, ***p<0.001, **** p<0.0001, ns, not significant.
Figure 3 : Analysis of pro-B cell iron in WT and mbl-cre ABCB7 cKO mice. Pro-B cells from WT and mbl-cre ABCB7 cKO mice were analyzed for Phen Green quenching for intracellular iron overload.
Figures 4A-4D: ABCB7-deficient pro-B cells had replication induced DNA damage. Figures 4A-4B) Bone marrow suspensions were incubated for 3 hours with EdU analyzed by FACS analysis along with phosphoH2A.X (Figure 4A) and quantified across experiments (Figure 4B). Figures 4C-4D) Percent and MFI of EdU+ cells after 3 hours of labeling are shown in (Figure 4C) and quantified in (Figure 4D). Figure 5: H&E of bone marrow from older/sick CD2-icre ABCB7 cKO mice as compared to age-matched WT or littermate controls.
Figure 6: Analysis of erythropoiesis using CD71 and Teri 19 in CD2-icre ABCB7 cKO mice as compared to age-matched WT or littermate controls.
Figure 7: CBC analysis of 4-5-month CD2-icre ABCB7 cKO mice as compared to age-matched WT or littermate controls. Data compared CBCs from 10 WT and 11 CD2-icre ABCB7 cKO mice. Statistical analysis was performed using Student’s t test. **p<0.01, *** p<0.001.
Figure 8: Analysis of myeloid populations in the spleen from CD2-icre ABCB7 cKO mice as compared to age-matched WT or littermate controls.
Figure 9: Similar frequencies and numbers of LSK cells in the bone marrow from older/sick CD2-icre ABCB7 cKO mice as compared to age-matched WT or littermate controls.
Figure 10: Analysis of splenic stress erythropoiesis using CD71 and Teri 19 in mbl- cre ABCB7 cKO mice as compared to age-matched WT or littermate controls.
Figure 11 : Analysis of myeloid populations in the spleen from mb 1 -ere ABCB7 cKO mice as compared to age-matched WT or littermate controls.
Figure 12: Upregulation of CD80 on bone marrow macrophages (CD1 lb+Ly6G’ F4/80+) from older/sick CD2-icre ABCB7 cKO mice as compared to age-matched ABCB711 fl littermate controls.
Figure 13: Expression of a LSL-Tomato (TMT) reporter in splenic B cells (top) macrophages (middle) or neutrophils (bottom) in LSL-Tomato CD2-icre ABCB7 cKO mice (right) as compared to LSL-Tomato CD2-icre (ABCB7 WT) mice (left).
Figure 14: Analysis of myeloid populations in the spleen from CD2-icre ABCB7 cKO mice and CD2-icre ABCB7 cKO/C/EBPa cKO as compared to age-matched ABCB7 floxed controls.
Figures 15A-15B: ABCB7 was required for erythropoiesis. Figure 15 A) Example of wild-type littermate and ErGFP-cre ABCB7 cKO embryos. Figure 15B) Flow cytometry analysis of erythropoiesis at el0.5. Left panel shows gating strategy for R1-R5 gates. ErGFP- cre ABCB7 cKO embryos had a block in erythropoiesis at the R3 CD71 high Teri 19+ stage. Figure 16: ABCB7-deficient pro-B cells had increased PARP1 expression. Analysis of PARP1 expression in Fr C/C' in pro-B cells from WT and mb 1 -ere ABCB7 cKO mice. Representative FACS analysis is shown at left and quantified at right.
Figure 17: Induction of myc-tagged ABCB7 by doxycycline (dox). Multipotent progenitors (MPPs) from rtTA ABCB7myc mice were expanded in culture, and treated with dox for 0, 1 or 2 days. Expression of myc-tagged ABCB7 was examined by Western blot with actin serving as a loading control.
DETAILED DESCRIPTION
This document provides methods and materials for treating myeloid disorders (e.g., SF3B1 -associated myeloid disorders). For example, this document provides methods and materials for using one or more inhibitors of early lymphopoiesis to treat a mammal (e g., a human) having a myeloid disorder (e.g., a SF3B1 -associated myeloid disorder). For example, one or more inhibitors of early lymphopoiesis can be administered to a mammal (e.g., a human) having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) to treat the mammal.
In some cases, when treating a mammal (e.g., a human) having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) as described herein, the methods do not include administering any intravenous immunoglobulin (IVIG) to the mammal.
When treating a mammal (e.g., a human) having a myeloid disorder (e.g., SF3B1- associated myeloid disorder) as described herein, the mammal can have any type of myeloid disorder. In some cases, a myeloid disorder can be a SF3B1 -associated myeloid disorder. In some cases, a myeloid disorder can be a MDS. In some cases, a myeloid disorder can be a MPN. In some cases, a myeloid disorder can include cell-extrinsic emergency myelopoiesis.
When treating a mammal (e.g., a human) having a SF3B1 -associated myeloid disorder as described herein, the SF3B1 -associated myeloid disorder can be any appropriate SF3B1 -associated myeloid disorder. In some cases, a SF3B1 -associated myeloid disorder can be a myeloid disorder that includes the expression of a modified SF3B1 polypeptide (e.g., a SF3B1 polypeptide having a K700E modification) by hematopoietic cells. In some cases, a SF3B1 -associated myeloid disorder can be a myeloid disorder that includes a reduced expression level of an ATP-binding cassette sub-family B member 7 (ABCB7) polypeptide by hematopoietic cells. The term “reduced level” as used herein with respect to a level of an ABCB7 polypeptide refers to any level that is lower than a reference level of the ABCB7 polypeptide. The term “reference level” as used herein with respect to a level of an ABCB7 polypeptide refers to the level of the ABCB7 polypeptide typically observed in a mammal that does not have a SF3B1 -associated myeloid disorder (e.g., a healthy mammal). For example, a SF3B1 -associated myeloid disorder can be a myeloid disorder that includes expression of a modified SF3B1 polypeptide (e.g., a SF3B1 polypeptide having a K700E modification) by hematopoietic cells, which can generate aberrant splicing of an ABCB7 messenger RNA (mRNA; e.g., between exons 8 and 9) leading to nonsense-mediated decay of the ABCB7 mRNA and a reduced level of expression of an ABCB7 polypeptide by hematopoietic cells. In some cases, a SF3B1 -associated myeloid disorder can be as described elsewhere (see, e.g., Mangaonkar et al., Haematol ogica, 107: 1189-1192 (2022); Venable et al., Am. J. Clin. Pathol., 156:679-690 (2021); Patnaik et al., Am. J. HematoL, 96:379-394 (2021); Patnaik et al., Am. J. HematoL, 92:297-310 (2017); and Wudhikarn et al., Blood Adv., 4:5716-5721 (2020)).
Any type of mammal having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) can be treated as described herein. Examples of mammals that can be treated with one or more inhibitors of early lymphopoiesis as described herein include, without limitation, humans, non-human primates (e.g., monkeys), dogs, cats, horses, cows, pigs, sheep, rabbits, mice, and rats. For example, a human having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) can be treated with one or more inhibitors of early lymphopoiesis as described herein.
In some cases, the methods provided herein can include identifying a mammal (e.g., a human) as having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder). Any appropriate method can be used to identify a mammal as having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder). For example, analysis of complete blood counts, blood smears, and/or bone marrow aspirates can be used to identify a human or other mammal as having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder).
A mammal having a myeloid disorder (e.g., SF3Bl-associated myeloid disorder) can be administered or instructed to self-administer one or more (e.g., one, two, three, four, or more) inhibitors of early lymphopoiesis described herein. As used herein, an “inhibitor of early lymphopoiesis” can be any agent that can target developing B cells (e.g., pro-B cells such as early pro-B cells and late pro-B cells) without targeting peripheral B cells. In some cases, an inhibitor of early lymphopoiesis can target (e.g., target and destroy) one or more B cell progenitor cells. For example, an inhibitor of early lymphopoiesis can target (e.g., target and destroy) a common lymphoid progenitor (CLP) cell. For example, an inhibitor of early lymphopoiesis can target (e.g., target and destroy) a pre-pro-B (PPB) cell. In some cases, an inhibitor of early lymphopoiesis can reduce or eliminate the transition of one or more B cell progenitor cells into B cells. For example, an inhibitor of early lymphopoiesis can reduce or eliminate the transition of a multipotent progenitor (MPP) cell into a B cell. For example, an inhibitor of early lymphopoiesis can reduce or eliminate the transition of a CLP cell into a B cell. For example, an inhibitor of early lymphopoiesis can reduce or eliminate the transition of a PPB cell into a B cell.
In some cases, an inhibitor of early lymphopoiesis can be an inhibitor of a fms like tyrosine kinase 3 (FLT3) polypeptide. An inhibitor of a FLT3 polypeptide can be an inhibitor of FLT3 polypeptide activity (e.g., anti-FLT3 antibodies such as neutralizing anti-FLT3 antibodies and small molecules that target a FLT3 polypeptide) or an inhibitor of FLT3 polypeptide expression (e.g., nucleic acid molecules designed to induce RNA interference (RNAi) of FLT3 polypeptide expression such as antisense oligonucleotides (ASOs), siRNA molecules, and shRNA molecules). In some cases, an inhibitor of a FLT3 polypeptide can be in the form of a bispecific antibody. In some cases, an inhibitor of a FLT3 polypeptide can be in the form of a proteolysis targeting chimera (PROTAC™). In some cases, an inhibitor of a FLT3 polypeptide can be in the form of a trispecific T cell activating construct (TriTAC™). In some cases, an inhibitor of a FLT3 polypeptide can be in the form of an antibody-drug conjugate (ADC). Examples of inhibitors of a FLT3 polypeptide that can be used to treat a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) as described herein can be as shown in Table 1.
Table 1. Inhibitors of FLT3 polypeptides.
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Additional inhibitors of a FLT3 polypeptide (e.g., nucleic acid molecules designed to induce RNAi against FLT3 polypeptide expression) can be designed based on any appropriate nucleic acid (e g., a mRNA) encoding a FLT3 polypeptide sequence. Examples of nucleic acids encoding a FLT3 polypeptide sequence include, without limitation, those set forth in National Center for Biotechnology Information (NCBI) accession no. NM 004119 (version NM_004119.3).
In some cases, in addition to or in place of an inhibitor of a FLT3 polypeptide, the methods provided herein can include administering one or more (e.g., one, two, three, four, or more) agents that can target (e.g., target and destroy) FLT3+ cells to a mammal (e.g., a human) having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) to treat the mammal. For example, T cells expressing (e.g., designed to express) a chimeric antigen receptor (CAR) that can target a FLT3 polypeptide (FLT3-CAR T cells), such as HEMO- CAR-T cells (see, e.g., hemogenyx.com), can be administered to a mammal (e.g., a human) having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) to target (e.g., target and destroy) FLT3+ cells within the mammal.
In some cases, an inhibitor of early lymphopoiesis can be an inhibitor of an interleukin 7 (IL-7) polypeptide. An inhibitor of an IL-7 polypeptide can be an inhibitor of IL-7 polypeptide activity (e g., anti-IL-7 antibodies such as neutralizing anti-IL-7 antibodies and small molecules that target an IL-7 polypeptide) or an inhibitor of IL-7 polypeptide expression (e.g., nucleic acid molecules designed to induce RNAi of IL-7 polypeptide expression such as ASOs, siRNA molecules, and shRNA molecules). In some cases, an inhibitor of an IL-7 polypeptide can be in the form of a bispecific antibody (e.g., a bispecific antibody that can target and bind both an IL-7 polypeptide and a programmed cell death protein 1 (PD-1) polypeptide such as a BiCKI®-IL-7 antibody). In some cases, an inhibitor of an IL-7 polypeptide can be in the form of a PROTAC™. In some cases, an inhibitor of an IL- 7 polypeptide can be in the form of a TriTAC™. In some cases, an inhibitor of an IL-7 polypeptide can be in the form of an ADC. Examples of inhibitors of an IL-7 polypeptide that can be used to treat a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) as described herein can be as shown in Table 2.
Table 2. Inhibitors of IL-7 polypeptides.
Figure imgf000015_0001
Additional inhibitors of an IL-7 polypeptide (e.g., nucleic acid molecules designed to induce RNAi against IL-7 polypeptide expression) can be designed based on any appropriate nucleic acid (e.g., a mRNA) encoding an IL-7 polypeptide sequence. Examples of nucleic acids encoding an IL-7 polypeptide sequence include, without limitation, those set forth in NCBI accession no. NM_001410734 (version NM_001410734. 1).
In some cases, an inhibitor of an IL-7 receptor (IL-7R; e.g., an IL7-Ra) can be used in place of or in addition to an inhibitor of an IL-7 polypeptide to treat a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) as described herein. Examples of inhibitors of an IL-7 receptor include, without limitation, GIFT-7, ASP-9801, BNT-152, ZB-168, ADX-914, bempikibart, lusvertikimab, KG-002, and B-12.
In some cases, in addition to or in place of an inhibitor of an IL-7 polypeptide, the methods provided herein can include administering one or more (e.g., one, two, three, four, or more) agents that can target (e.g., target and destroy) IL-7+ cells to a mammal (e g., a human) having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) to treat the mammal. For example, T cells expressing (e.g., designed to express) a CAR that can target a melanoma-associated antigen 4 (MAEG-4) polypeptide and expressing an IL-7 polypeptide can be administered to a mammal (e.g., a human) having a myeloid disorder (e.g., SF3B1- associated myeloid disorder) to target (e.g., target and destroy) IL-7+ cells within the mammal. For example, lymphocytes (e.g., tumor-infiltrating lymphocytes) expressing (e.g., designed to express) an IL-7 polypeptide can be administered to a mammal (e.g., a human) having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) to target (e.g., target and destroy) IL-7+ cells within the mammal. For example, one or more agents designed to induce an immune response against an IL-7 polypeptide (e.g., a virus (e.g., an oncolytic virus such as a vaccinia virus) encoding an IL-7 polypeptide) can be administered to a mammal (e.g., a human) having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) to target (e.g., target and destroy) IL-7+ cells within the mammal.
In some cases, in addition to or in place of an inhibitor of an IL-7R polypeptide (e g., an IL-7Ra polypeptide, the methods provided herein can include administering one or more (e.g., one, two, three, four, or more) agents that can target (e.g., target and destroy) IL-7R+ cells (e.g., IL-7Ra cells) to a mammal (e.g., a human) having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) to treat the mammal. For example, T cells expressing (e.g., designed to express) a CAR that can target a CD19 polypeptide and expressing an IL-7 polypeptide can be administered to a mammal (e.g., a human) having a myeloid disorder (e.g., SF3Bl-associated myeloid disorder) to target (e.g., target and destroy) IL-7Ra+ cells within the mammal.
In some cases, an inhibitor of early lymphopoiesis can be as described elsewhere (see, e.g., Medina, Int. J. Mol. Sci., 23(13):7289 (2022); Medina et al., Curr. Opin. Hematol., 12(3):203-9 (2005); Sun et al., Biomed. Pharmacother ., 169: 115905 (2023); Wang et al., Future Med. Chem., 15( 1): 57-71 (2023); Zhang et al., Bioorg. Med. Chem. Lett., 30(22): 127532 (2020); Yuan et al., Eur. J. Med. Chem., 178:468-483 (2019); Austin et al., Cancer Res., 81 (13_Supplement): Abstract 913 (2021); and Wang et al., Eur. J. Med. Chem., 268: 116237 (2024)).
One or more inhibitors of early lymphopoiesis described herein can be formulated into a composition (e.g., a pharmaceutically acceptable composition) for administration to a mammal having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder). For example, a therapeutically effective amount of one or more inhibitors of early lymphopoiesis described herein can be formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. A pharmaceutical composition can be formulated for administration in solid or liquid form including, without limitation, sterile solutions, suspensions, sustained-release formulations, tablets, capsules, pills, powders, and granules. A composition (e.g., a pharmaceutically acceptable composition) including one or more inhibitors of early lymphopoiesis described herein can be administered locally or systemically. A composition containing one or more inhibitors of early lymphopoiesis described herein can be designed for oral or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal). For example, a composition containing one or more inhibitors of early lymphopoiesis described herein can be administered systemically by an oral administration to or inhalation by a mammal (e.g., a human). When being administered orally, a composition containing one or more inhibitors of early lymphopoiesis described herein can be in the form of a pill, tablet, or capsule.
In some cases, one or more (e.g., one, two, three, four, or more) inhibitors of early lymphopoiesis can be used to reduce the severity of one or more symptoms of a myeloid disorder (e.g., SF3B1 -associated myeloid disorder). For example, one or more inhibitors of early lymphopoiesis can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having a myeloid disorder such as a SF3B1 -associated myeloid disorder) to reduce the severity of one or more symptoms of the myeloid disorder. Examples of symptoms of myeloid disorders (e.g., SF3B1 -associated myeloid disorders) include, without limitation, fatigue, shortness of breath, pallor, easy or unusual bruising or bleeding, pinpoint-sized red spots just beneath the skin that are caused by bleeding, frequent infections, weakness, lightheadedness, and fever. In some cases, the methods and materials described herein can be effective to reduce the severity of one or more symptoms of a myeloid disorder (e.g., SF3B1- associated myeloid disorder) in a mammal having a myeloid disorder (e.g., SF3Bl-associated myeloid disorder) by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.
In some cases, one or more (e.g., one, two, three, four, or more) inhibitors of early lymphopoiesis can be used to reduce myelopoiesis. For example, one or more inhibitors of early lymphopoiesis can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having a myeloid disorder such as a SF3B1 -associated myeloid disorder) to reduce myelopoiesis within the mammal. In some cases, the methods and materials described herein can be effective to reduce myelopoiesis in a mammal having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. In some cases, the methods and materials described herein can be effective to reduce myelopoiesis in a mammal having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) such that a blood sample obtained from the mammal after being administered one or more inhibitors of early lymphopoiesis as described herein includes a red blood cell (RBC) count of at least 3.9 million cells per microliter (pL) of blood. For example, the methods and materials described herein can be effective to reduce myelopoiesis in a mammal having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) such that a blood sample obtained from the mammal after being administered one or more inhibitors of early lymphopoiesis as described herein includes a RBC count of from about 3.9 million cells to about 5.6 million cells per pL of blood (e.g., from about 3.9 million cells to about 5 million cells, from about 3.9 million cells to about 4.5 million cells, from about 3.9 million cells to about 4.2 million cells, from about 4 million cells to about 5.6 million cells, from about 4.2 million cells to about 5.6 million cells, from about 4.5 million cells to about 5.6 million cells, from about 4.8 million cells to about 5.6 million cells, from about 5.1 million cells to about 5.6 million cells, from about 4.1 million cells to about 5.2 million cells, from about 4.4 million cells to about 4.8 million cells, from about 4 million cells to about 4.5 million cells, from about 4.5 million cells to about 5 million cells, or from about 5 million cells to about 5.5 million cells per pL of blood).
In some cases, one or more inhibitors of early lymphopoiesis described herein can be used as the sole active agent to treat a mammal (e.g., a human) having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder).
In some cases, one or more inhibitors of early lymphopoiesis described herein can be administered to a mammal (e.g., a human) having a myeloid disorder (e.g., SF3B1 -associated myeloid disorder) together with one or more (e.g., one, two, three, four, or more) additional agents/therapies used to treat a myeloid disorder (or to treat one or more symptoms of a myeloid disorder). Examples of agents that can be used to treat a myeloid disorder (or to treat one or more symptoms of a myeloid disorder) include, without limitation, azacytidine (e.g., ONUREG® and VID AZA®), decitabine, erythropoietin (EPO), lenalidomide, and any combinations thereof. In cases where one or more inhibitors of early lymphopoiesis described herein are used in combination with one or more additional agents used to treat a myeloid disorder, the one or more additional agents can be administered at the same time (e g., in a single composition containing one or more inhibitors of early lymphopoiesis described herein and the one or more additional agents) or independently. For example, one or more inhibitors of early lymphopoiesis described herein can be administered first, and the one or more additional agents administered second, or vice versa. Examples of therapies that can be used to treat a myeloid disorder (or to treat one or more symptoms of a myeloid disorder) include, without limitation, blood transfusions and bone marrow transplants. In cases where one or more inhibitors of early lymphopoiesis described herein used in combination with one or more additional therapies used to treat a myeloid disorder (or to treat one or more symptoms of a myeloid disorder), the one or more additional therapies can be performed at the same time or independently of the administration of one or more inhibitors of early lymphopoiesis described herein. For example, one or more inhibitors of early lymphopoiesis described herein can be administered before, during, or after the one or more additional therapies are performed.
The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.
EXAMPLES
Example 1: SF3B1 -associated myelodysplasia is and decreased expression of ABCB7 in B- lineage precursor cells
This Examples describes the discovery that myelodysplasia in patients with SF3B1- associated myelodysplastic disorders is not strictly cell-intrinsic, but instead is mediated by decreased expression of ABCB7 in B-lineage precursor cells. See, e.g., Figure 1.
ABCB7 is required for B cell development beyond the pro-B cell stage
To determine the role of ABCB7 in regulating B lymphocyte development and differentiation, 3 lines of ABCB7 conditional knockout (cKO) mice were generated to analyze the function of ABCB7 at different steps of lymphopoiesis: CD2-icre (deletion initiates in early lymphocyte development), mb 1 -ere (deletion initiates during B cell specification), and CD23-cre (deletion initiates at the T2 stage of peripheral B cell maturation). Virtually no IgM+ cells were detected in the bone marrow (Hardy Fr. E or Fr. F). Examination of absolute cell numbers demonstrated that while there were fewer Fr. B and Fr. C cells, there was a block leading to a large decrease of 100- to 1000-fold in absolute cell number in Fr. D-F in mbl-cre ABCB7 cKO mice compared to ABCB7fl/fl littermates (Figure 2). Consistent with the severe block in B cell development, there was approximately 1000- fold fewer peripheral B cells in mb 1 -ere ABCB7 cKO mice (Figure 2). Peripheral B cell phenotypic populations were unaffected in CD23-cre ABCB7 cKO mice (Figure 2), indicating that ABCB7 was not required for B cell survival or homeostasis. The transition from Fr. C to C' depends on successful navigation of the pre-BCR checkpoint. The expression of intracellular p heavy chain (pHC) in B220+CD19+CD43+ B cells was examined and it was found that while pro-B cells from ABCB7 fl/fl mice expressed intracellular pHC, while very few pro-B cells from or mb 1 -ere ABCB7 cKO mice expressed intracellular pHC.
Loss of ABCB7 leads to iron overload and replication-induced DNA damage
It was examined whether the inability to proceed through the pre-BCR checkpoint was due to increased apoptosis or cell death. B220+CD19+CD43+ pro-B cells were stained with Annexin V as well as a fixable viability dye (FVD). There was no increase in apoptosis or cell death in ABCB7-deficient B cell precursors. As ABCB7 is an iron transporter, it was examined whether there was an increase in intracellular iron in ABCB7-deficient pro-B cells. Phen Green staining was quenched in ABCB7-deficient pro-B cells as compared to WT pro- B cells, indicating increased concentrations of intracellular metal ions, consistent with iron overload and a disruption in iron homeostasis (Figure 3). ABCB7-deficient pro-B cells had increased expression of phospho-H2AX, which accumulates at sites of DNA damage (Figures 4A-4B). This increase was primarily found in proliferating pro-B cells, as demonstrated by EdU incorporation (Figures 4A-4B). Both the percent and rate of EdU incorporation was also decreased in ABCB7-deficient pro-B cells, indicating that there appears to be a defect in DNA replication (Figures 4C-4D). These data suggest that DNA- damaged ABCB7-deficient B cells can produce a danger signal or inflammation in the bone marrow leading to cell-extrinsic effects on hematopoiesis.
Loss of bone marrow erythropoiesis and enhanced myelopoiesis in CD2-icre ABCB7 cKO and mbl-cre ABCB7 cKO mice
Although initially healthy, all mbl-cre ABCB7 cKO mice and CD2-icre ABCB7 cKO mice underwent a progressive anemia, with pronounced runting and a disheveled and hunched appearance, necessitating their euthanasia at approximately 4-5 months of age. H&E of bone marrow of CD2-icre ABCB7 cKO mice revealed a dramatic shift in hematopoiesis, with few erythroid islands present and a predominance of myeloid cells (Figure 5). The severe block in bone marrow erythropoiesis was confirmed by flow cytometry, with few CD71+Terl l9+ erythroblasts present (Figure 6) and anemia (Figure 7). To compensate, CD2- icre ABCB7 cKO mice initiated splenic stress erythropoiesis (Figure 6). The spleen was enlarged, with a significant increase in both monocytes (Ly6ChlLy6G‘) and neutrophils (LyG6+). There was a population of “left- shifted” (Ly6G10) immature neutrophils in the spleen, indicating dysregulated myelopoiesis (Figure 8). Bone marrow cellularity as unaffected in CD2-icre ABCB7 cKO mice and the LSK (Lineage’Scal+cKit+) population, which contains hematopoietic stem cells (HSCs) and early hematopoietic progenitors, was intact in CD2-cre ABCB7 cKO mice in terms of frequency and number, indicating that hematopoietic progenitors were maintained (Figure 9). The same changes in erythropoiesis and myelopoiesis were observed in mbl-cre ABCB7 cKO mice, which have deletions only in B cell precursors (Figure 10 and Figure 11). This shift in hematopoietic production resembled emergency or damage-induced myelopoiesis.
Myeloid expansion in CD2-icre ABCB7 cKO mice is cell extrinsic
In emergency myelopoiesis, severe infection leads to production of large quantities of myeloid cells. Bone marrow macrophages from CD2-icre ABCB7 cKO mice had increased expression of CD80, indicative of activation (Figure 12). CD2-icre deleted primarily in lymphocyte lineages, and mbl-cre deletion was limited to B cell progenitors, indicating that the macrophage activation and emergency myelopoiesis observed was likely cell-extrinsic. To test this, CD2-icre ABCB7 cKO mice were interbred with a lox-stop-lox (LSL) Tomato reporter mouse such that all cells that expressed ere, or that had a progenitor that expressed ere, expressed the Tomato reporter. While CD19+ B cells were efficiently labelled with the reporter, monocytes, macrophages, or neutrophils in CD2-icre ABCB7 cKO mice primarily lacked reporter expression (Figure 13). These results demonstrated that the effects on myelopoiesis were cell-extrinsic and not mediated by cre-deletion. To confirm this further, CD2-icre ABCB7 cKO/C/EBPa cKO mice were generated. C/EBPa is required for macrophage and neutrophil development, and CD2-icre deletion was restricted to lymphocytes, such that if there is cre-deletion occurring in myeloid precursors, then myelopoiesis is disrupted in CD2-icre ABCB7 cKO/C/EBPa cKO mice. However, the myeloid expansion was maintained in CD2-icre ABCB7 cKO/C/EBPo. cKO mice (Figure 14), demonstrating the myeloid expansion was independent of cre-mediated deletion. In addition, it was confirmed that there is no alteration in myelopoiesis in CD2-icre C/EBPa cKO mice. The absence of ABCB7 led to chronic cytokine or danger signals that were progressive and stimulating myelopoiesis. These results suggested that the loss of ABCB7 in the B cell lineage led to cell extrinsic effects driving enhanced myelopoiesis in the bone marrow, disrupted bone marrow erythropoiesis, and led to stress erythropoiesis in the spleen.
Cell-intrinsic requirement for ABCB7 in primitive erythropoiesis
To examine the role of ABCB7 specifically in the erythroid lineage, ABCB7 floxed mice were interbred with ErGFP-cre mice in which GFP -tagged ere was knocked into the erythropoietin receptor locus, restricting expression of ere exclusively to the erythroid lineage and no other hematopoietic lineage. The resulting litters lacked any ErGFP-cre ABCB7 cKO pups at weaning or at birth, indicating that the loss of ABCB7 in the erythroid lineage results in embryonic lethality. Using timed matings, ErGFP-cre ABCB7 cKO embryos were found to die at approximately embryonic day e 10.5- 11, with noted pallor and fetal liver anemia (Figure 15A). To characterize the block in erythropoiesis, single cell suspensions from whole wild-type and ErGFP-cre ABCB7 cKO embryos at el0.5 were obtained by dissecting the embryos away from the amniotic sac and placenta and gently teasing apart the embryonic tissues, and the single cells suspensions were examined by flow cytometry. Using CD71 and Teri 19, the cells were divided into 5 gates (R1 through R5, shown schematically in Fig 15B) to define EryP from most immature to most mature: R1 (CD71medTerl 19-) contains early erythroid progenitors and proerythroblasts; R2 (CD71hlshTerl l9‘/low) contains pro-erythroblasts and early basophilic erythroblasts; R3 (CD71hlghTerl 19+) contains basophilic erythroblasts; R4 (CD71medTerl 19+) contains chromatophilic and orthochromatophilic erythroblasts; and R5 (CD71lowTerl l9+) contains late orthochromatophilic erythroblasts. Cells were first gated on large macrocytic cells by size, to exclude any enucleated cells which would have been maternally derived. Examination of erythropoiesis at el0.5 showed that in contrast to WT littermates, ErGFP-cre ABCB7 cKO embryos had a severe block in erythropoiesis, leading to a block at the R2 (CD71hlghTerl 19+) stage. These data suggest that ABCB7 was required in a cell intrinsic manner for primitive erythropoiesis, prior to the generation of sideroblasts.
Danger signal in ABCB7-deficient -B cells
ABCB7-deficient pro-B cells were examined and upregulation of PARP1 protein was found by flow cytometry (Figure 16). Therefore, the increased DNA damage present in ABCB7-deficient pro-B cells may lead to a danger signal through PARP1 -mediated HMGB1 release.
Effects of decreased expression of ABCB7 on hematopoiesis
A dox-regulated myc-tagged allele of ABCB7 (hereafter called ABCB7-myc) was generated. In brief, a myc-tagged ABCB7 cDNA was inserted downstream of a minimal promoter regulated by Tet-responsive elements engineered upstream. This plasmid also contained FRT sites for homologous recombination in engineered ES cells for insertion into the Col Al locus. Targeted ES cells were generated, and germline transmission has been achieved. To confirm dox-regulation of this allele, rtTA ABCB7myc mice were generated. Hematopoietic progenitors from rtTA ABCB7myc mice were expanded in culture and treated with dox or left untreated. As shown in Figure 17, dox treatment led to expression of myc- tagged ABCB7, confirming that a mouse with a dox-regulated allele of ABCB7 was generated.
Example 2: Treating myeloid disorders
A human identified as having a SF3B1 -associated myeloid disorder is administered one or more inhibitors of early lymphopoiesis (e.g., midostaurin, gilteritinib, quizartinib, sorafenib, sunitinib, lestaurtinib, tandutinib, crenolanib, AIU2008, ALLO-819, BGS-2456, BMF-500, CCT245718, CDDD11-8, CHMFL-FLT3-213, CHMFL-FLT3-335, clifutinib besylate, CLN-049, CRBN(FLT3)-8, crenolanib besylate, creserol, CTS-2016, cytarabine/daunorubicin, D-64406, D-65476, danatinib, dapolsertib, E2082-0047, E-6201, EC-70124, EP-0042, ETH-155036, gilteritinib fumarate, H-104, H-118, HD-10019, HEC- 73543, HP1328, HPB-092, HSD1169, HSK-205, HSN-431, HYML-122, JH-IX-179, K783- 0308, KRX-107, KWB-201, LGR-3922, LNX-231, lomonitinib, LT- 171-861, LT-540-717, LT-850-166, luxeptinib, LWY713, MIC135, MRX-2843, MZH29, NCGC-1481, nefextinib, ningetinib tosylate, nintedanib esylate, ON- 150030, pacritinib, PHI-101, PLD-102, PLM- 102, pluripotin, quizartinib hydrochloride, RF-1302, ruserontinib, SENTI-202, SKLB-677, SLX 0953, sorafenib tosylate, STI-8591, T-1301, TLX83, TP-P1, TSD204, TSN-084, TT- 00973, tuspetinib, XY0206, GSK2618960, ADX-914, PF-06342674, GIFT-7, ASP-9801, BNT-152, GSK-3888130B, KG-002, FT-873, HCW-9206, GIFT-7, ASP-9801, BNT-152,
ZB-168, ADX-914, bempikibart, lusvertikimab, KG-002, and/or B-12). The administered inhibitor(s) can reduce the severity of one or more symptoms of a SF3B1 -associated myeloid disorder (e.g., fatigue, shortness of breath, pallor, easy or unusual bruising or bleeding, pinpoint-sized red spots just beneath the skin that are caused by bleeding, frequent infections, weakness, lightheadedness, and/or fever).
OTHER EMBODIMENTS
It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:
1. A method for treating a splicing factor 3B subunit 1 (SF3Bl)-associated myeloid disorder, wherein said method comprises administering an inhibitor of early lymphopoiesis to a mammal identified as having said SF3B1 -associated myeloid disorder.
2. The method of claim 1, wherein said mammal is a human.
3. The method of any one of claims 1-2, wherein hematopoietic cells of said mammal express a reduced level of an ATP-binding cassette sub-family B member 7 (ABCB7) polypeptide as compared to the level of expression of said ABCB7 polypeptide by hematopoietic cells of a healthy mammal not having said SF3B1 -associated myeloid disorder.
4. The method of any one of claims 1-3, wherein said SF3B1 -associated myeloid disorder is a SF3B1 -associated myelodysplastic syndrome.
5. The method of any one of claims 1-3, wherein said SF3B1 -associated myeloid disorder is a SF3B1 -associated myeloproliferative disorder.
6. The method of any one of claims 1-5, wherein said inhibitor of early lymphopoiesis is selected from the group consisting of midostaurin, gilteritinib, quizartinib, sorafenib, sunitinib, lestaurtinib, tandutinib, crenolanib, GSK2618960, ADX-914, and PF-06342674.
7. The method of any one of claims 1-5, wherein said inhibitor of early lymphopoiesis is selected from the group consisting of AIU2008, ALLO-819, BGS-2456, BMF-500, CCT245718, CDDD11-8, CHMFL-FLT3-213, CHMFL-FLT3-335, clifutinib besylate, CLN- 049, CRBN(FLT3)-8, crenolanib besylate, creserol, CTS-2016, cytarabine/daunorubicin, D- 64406, D-65476, danatinib, dapolsertib, E2082-0047, E-6201, EC-70124, EP-0042, ETH- 155036, gilteritinib fumarate, H-104, H-118, HD-10019, HEC-73543, HP1328, HPB-092, HSD1169, HSK-205, HSN-431, HYML-122, JH-IX-179, K783-0308, KRX-107, KWB-201, LGR-3922, LNX-231, lomonitinib, LT-171-861, LT-540-717, LT-850-166, luxeptinib, LWY713, MIC135, MRX-2843, MZH29, NCGC-1481, nefextinib, ningetinib tosylate, nintedanib esylate, ON-150030, pacritinib, PHI-101, PLD-102, PLM-102, pluripotin, quizartinib hydrochloride, RF-1302, ruserontinib, SENTI-202, SKLB-677, SLX 0953, sorafenib tosylate, STI-8591, T-1301, TLX83, TP-P1, TSD204, TSN-084, TT-00973, tuspetinib, XY0206, GIFT-7, ASP-9801, BNT-152, GSK-3888130B, KG-002, FT-873, HCW-9206, GIFT-7, ASP-9801, BNT-152, ZB- 168, ADX-914, bempikibart, lusvertikimab, KG-002, and B-12.
8. A method for treating a mammal having a splicing factor 3B subunit 1 (SF3B1)- associated myeloid disorder, wherein said method comprises administering an inhibitor of early lymphopoiesis to said mammal.
9. The method of claim 8, wherein said mammal is a human.
10. The method of any one of claims 8-9, wherein hematopoietic cells of said mammal express a reduced level of an ATP-binding cassette sub-family B member 7 (ABCB7) polypeptide as compared to the level of expression of said ABCB7 polypeptide by hematopoietic cells of a healthy mammal not having said SF3B1 -associated myeloid disorder.
11. The method of any one of claims 8-10, wherein said SF3B1 -associated myeloid disorder is a SF3B1 -associated myelodysplastic syndrome.
12. The method of any one of claims 8-10, wherein said SF3B1 -associated myeloid disorder is a SF3B1 -associated myeloproliferative disorder.
13. The method of any one of claims 8-12, wherein said inhibitor of early lymphopoiesis is selected from the group consisting of midostaurin, gilteritinib, quizartinib, sorafenib, sunitinib, lestaurtinib, tandutinib, crenolanib, GSK2618960, ADX-914, and PF-06342674.
14. The method of any one of claims 8-12, wherein said inhibitor of early lymphopoiesis is selected from the group consisting of AIU2008, ALLO-819, BGS-2456, BMF-500, CCT245718, CDDD11-8, CHMFL-FLT3-213, CHMFL-FLT3-335, clifutinib besylate, CLN- 049, CRBN(FLT3)-8, crenolanib besylate, creserol, CTS-2016, cytarabine/daunorubicin, D- 64406, D-65476, danatinib, dapolsertib, E2082-0047, E-6201, EC-70124, EP-0042, ETH- 155036, gilteritinib fumarate, H-104, H-118, HD-10019, HEC-73543, HP1328, HPB-092, HSD1169, HSK-205, HSN-431, HYML-122, JH-IX-179, K783-0308, KRX-107, KWB-201, LGR-3922, LNX-231, lomonitinib, LT-171-861, LT-540-717, LT-850-166, luxeptinib, LWY713, MIC135, MRX-2843, MZH29, NCGC-1481, nefextinib, ningetinib tosylate, nintedanib esylate, ON-150030, pacritinib, PHI-101, PLD-102, PLM-102, pluripotin, quizartinib hydrochloride, RF-1302, ruserontinib, SENTI-202, SKLB-677, SLX 0953, sorafenib tosylate, STI-8591, T-1301, TLX83, TP-P1, TSD204, TSN-084, TT-00973, tuspetinib, XY0206, GIFT-7, ASP-9801, BNT-152, GSK-3888130B, KG-002, FT-873, HCW-9206, GIFT-7, ASP-9801, BNT-152, ZB- 168, ADX-914, bempikibart, lusvertikimab, KG-002, and B- 12.
15. The use of a composition comprising an inhibitor of early lymphopoiesis to treat a splicing factor 3B subunit 1 (SF3Bl)-associated myeloid disorder.
16. The use of claim 15, wherein said SF3B1 -associated myeloid disorder is a SF3B1- associated myelodysplastic syndrome.
17. The use of claim 15, wherein said SF3B1 -associated myeloid disorder is a SF3B1- associated myeloproliferative disorder.
18. The use of any one of claims 15-17, wherein said inhibitor of early lymphopoiesis is selected from the group consisting of midostaurin, gilteritinib, quizartinib, sorafenib, sunitinib, lestaurtinib, tandutinib, crenolanib, GSK2618960, ADX-914, and PF-06342674.
19. The use of any one of claims 15-17, wherein said inhibitor of early lymphopoiesis is selected from the group consisting of AIU2008, ALLO-819, BGS-2456, BMF-500, CCT245718, CDDD11-8, CHMFL-FLT3-213, CHMFL-FLT3-335, clifutinib besylate, CLN- 049, CRBN(FLT3)-8, crenolanib besylate, creserol, CTS-2016, cytarabine/daunorubicin, D- 64406, D-65476, danatinib, dapolsertib, E2082-0047, E-6201, EC-70124, EP-0042, ETH- 155036, gilteritinib fumarate, H-104, H-118, HD-10019, HEC-73543, HP1328, HPB-092, HSD1169, HSK-205, HSN-431, HYML-122, JH-IX-179, K783-0308, KRX-107, KWB-201, LGR-3922, LNX-231, lomonitinib, LT-171-861, LT-540-717, LT-850-166, luxeptinib, LWY713, MIC135, MRX-2843, MZH29, NCGC-1481, nefextinib, ningetinib tosylate, nintedanib esylate, ON-150030, pacritinib, PHI-101, PLD-102, PLM-102, pluripotin, quizartinib hydrochloride, RF-1302, ruserontinib, SENTI-202, SKLB-677, SLX 0953, sorafenib tosylate, STI-8591, T-1301, TLX83, TP-P1, TSD204, TSN-084, TT-00973, tuspetinib, XY0206, GIFT-7, ASP-9801, BNT-152, GSK-3888130B, KG-002, FT-873, HCW-9206, GIFT-7, ASP-9801, BNT-152, ZB- 168, ADX-914, bempikibart, lusvertikimab, KG-002, and B- 12.
20. An inhibitor of early lymphopoiesis for use in the preparation of a medicament to treat a splicing factor 3B subunit 1 (SF3Bl)-associated myeloid disorder.
21. An inhibitor of early lymphopoiesis for use in the treatment of a splicing factor 3B subunit 1 (SF3Bl)-associated myeloid disorder.
22. The inhibitor of any one of claims 20-21, wherein said SF3Bl-associated myeloid disorder is a SF3B1 -associated myelodysplastic syndrome.
23. The inhibitor of any one of claims 20-21, wherein said SF3B1 -associated myeloid disorder is a SF3B1 -associated myeloproliferative disorder.
24. The inhibitor of any one of claims 20-23, wherein said inhibitor of early lymphopoiesis is selected from the group consisting of midostaurin, gilteritinib, quizartinib, sorafenib, sunitinib, lestaurtinib, tandutinib, crenolanib, GSK2618960, ADX-914, and PF- 06342674.
25. The inhibitor of any one of claims 20-23, wherein said inhibitor of early lymphopoiesis is selected from the group consisting of AIU2008, ALLO-819, BGS-2456, BMF-500, CCT245718, CDDD11-8, CHMFL-FLT3-213, CHMFL-FLT3-335, clifutinib besylate, CLN-049, CRBN(FLT3)-8, crenolanib besylate, creserol, CTS-2016, cytarabine/daunorubicin, D-64406, D-65476, danatinib, dapolsertib, E2082-0047, E-6201, EC-70124, EP-0042, ETH-155036, gilteritinib fumarate, H-104, H-118, HD-10019, HEC- 73543, HP 1328, HPB-092, HSD1169, HSK-205, HSN-431, HYML-122, JH-IX-179, K783- 0308, KRX-107, KWB-201, LGR-3922, LNX-231, lomonitinib, ET- 171-861, LT-540-717, LT-850-166, luxeptinib, LWY713, MIC135, MRX-2843, MZH29, NCGC-1481, nefextinib, ningetinib tosylate, nintedanib esylate, ON- 150030, pacritinib, PHI-101, PLD-102, PLM- 102, pluripotin, quizartinib hydrochloride, RF-1302, ruserontinib, SENTI-202, SKLB-677, SLX 0953, sorafenib tosylate, STI-8591, T-1301, TLX83, TP-P1, TSD204, TSN-084, TT- 00973, tuspetinib, XY0206, GIFT-7, ASP-9801, BNT-152, GSK-3888130B, KG-002, FT- 873, HCW-9206, GIFT-7, ASP-9801, BNT-152, ZB-168, ADX-914, bempikibart, lusvertikimab, KG-002, and B-12.
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