WO2010059779A1 - Cellule t11 en tant que régulateur transcriptionnel - Google Patents
Cellule t11 en tant que régulateur transcriptionnel Download PDFInfo
- Publication number
- WO2010059779A1 WO2010059779A1 PCT/US2009/065072 US2009065072W WO2010059779A1 WO 2010059779 A1 WO2010059779 A1 WO 2010059779A1 US 2009065072 W US2009065072 W US 2009065072W WO 2010059779 A1 WO2010059779 A1 WO 2010059779A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tell
- cells
- activator protein
- subject
- treating
- Prior art date
Links
- 230000002103 transcriptional effect Effects 0.000 title description 5
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims abstract description 59
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims abstract description 57
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims abstract description 56
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 30
- 239000000203 mixture Substances 0.000 claims abstract description 25
- 201000010099 disease Diseases 0.000 claims abstract description 22
- 238000011282 treatment Methods 0.000 claims abstract description 10
- 108010018242 Transcription Factor AP-1 Proteins 0.000 claims description 107
- 210000004027 cell Anatomy 0.000 claims description 85
- 230000000694 effects Effects 0.000 claims description 31
- 108010057466 NF-kappa B Proteins 0.000 claims description 25
- 230000014509 gene expression Effects 0.000 claims description 25
- 230000002401 inhibitory effect Effects 0.000 claims description 20
- 241000124008 Mammalia Species 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 230000037361 pathway Effects 0.000 claims description 13
- 230000004913 activation Effects 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 241000282414 Homo sapiens Species 0.000 claims description 10
- 108090000623 proteins and genes Proteins 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- 230000003278 mimic effect Effects 0.000 claims description 9
- 230000003213 activating effect Effects 0.000 claims description 8
- 239000000090 biomarker Substances 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 230000002018 overexpression Effects 0.000 claims description 8
- 102000004169 proteins and genes Human genes 0.000 claims description 8
- 238000002560 therapeutic procedure Methods 0.000 claims description 7
- 206010067671 Disease complication Diseases 0.000 claims description 6
- 108091000080 Phosphotransferase Proteins 0.000 claims description 6
- 208000000389 T-cell leukemia Diseases 0.000 claims description 6
- 230000000670 limiting effect Effects 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 102000020233 phosphotransferase Human genes 0.000 claims description 6
- 230000004044 response Effects 0.000 claims description 6
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 claims description 5
- 206010042971 T-cell lymphoma Diseases 0.000 claims description 5
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 5
- 239000005557 antagonist Substances 0.000 claims description 5
- 238000011161 development Methods 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 4
- 108010033276 Peptide Fragments Proteins 0.000 claims description 4
- 102000007079 Peptide Fragments Human genes 0.000 claims description 4
- 230000003993 interaction Effects 0.000 claims description 4
- 210000003519 mature b lymphocyte Anatomy 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 230000035755 proliferation Effects 0.000 claims description 3
- 230000019491 signal transduction Effects 0.000 claims description 3
- 230000001632 homeopathic effect Effects 0.000 claims description 2
- 239000002417 nutraceutical Substances 0.000 claims description 2
- 235000021436 nutraceutical agent Nutrition 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 claims description 2
- 102100023118 Transcription factor JunD Human genes 0.000 claims 38
- 102100023050 Nuclear factor NF-kappa-B p105 subunit Human genes 0.000 claims 6
- 238000003745 diagnosis Methods 0.000 abstract description 2
- 238000004393 prognosis Methods 0.000 abstract 1
- 102100023132 Transcription factor Jun Human genes 0.000 description 93
- 101001050288 Homo sapiens Transcription factor Jun Proteins 0.000 description 24
- 102000003945 NF-kappa B Human genes 0.000 description 19
- 102220135902 rs61731470 Human genes 0.000 description 16
- 239000013598 vector Substances 0.000 description 16
- 102100038885 Histone acetyltransferase p300 Human genes 0.000 description 15
- 102100027584 Protein c-Fos Human genes 0.000 description 15
- 108010071563 Proto-Oncogene Proteins c-fos Proteins 0.000 description 15
- 108091008611 Protein Kinase B Proteins 0.000 description 14
- 238000002474 experimental method Methods 0.000 description 14
- 230000006870 function Effects 0.000 description 13
- 238000001114 immunoprecipitation Methods 0.000 description 13
- 238000001262 western blot Methods 0.000 description 12
- 230000001225 therapeutic effect Effects 0.000 description 10
- 230000001419 dependent effect Effects 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 108020004414 DNA Proteins 0.000 description 8
- 230000006907 apoptotic process Effects 0.000 description 8
- 238000000749 co-immunoprecipitation Methods 0.000 description 8
- 102220122551 rs199798095 Human genes 0.000 description 8
- 101150026829 JUNB gene Proteins 0.000 description 7
- 238000010166 immunofluorescence Methods 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000013518 transcription Methods 0.000 description 7
- 230000035897 transcription Effects 0.000 description 7
- QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 description 7
- QDLHCMPXEPAAMD-UHFFFAOYSA-N wortmannin Natural products COCC1OC(=O)C2=COC(C3=O)=C2C1(C)C1=C3C2CCC(=O)C2(C)CC1OC(C)=O QDLHCMPXEPAAMD-UHFFFAOYSA-N 0.000 description 7
- 241000283707 Capra Species 0.000 description 6
- 101001113483 Homo sapiens Poly [ADP-ribose] polymerase 1 Proteins 0.000 description 6
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 6
- 230000001640 apoptogenic effect Effects 0.000 description 6
- 210000003719 b-lymphocyte Anatomy 0.000 description 6
- 230000035772 mutation Effects 0.000 description 6
- 230000009089 cytolysis Effects 0.000 description 5
- 230000003831 deregulation Effects 0.000 description 5
- 102000039446 nucleic acids Human genes 0.000 description 5
- 108020004707 nucleic acids Proteins 0.000 description 5
- 150000007523 nucleic acids Chemical class 0.000 description 5
- 238000012163 sequencing technique Methods 0.000 description 5
- 238000001890 transfection Methods 0.000 description 5
- PHEDXBVPIONUQT-UHFFFAOYSA-N Cocarcinogen A1 Natural products CCCCCCCCCCCCCC(=O)OC1C(C)C2(O)C3C=C(C)C(=O)C3(O)CC(CO)=CC2C2C1(OC(C)=O)C2(C)C PHEDXBVPIONUQT-UHFFFAOYSA-N 0.000 description 4
- 101150099271 FHIT gene Proteins 0.000 description 4
- 230000003081 coactivator Effects 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 230000008506 pathogenesis Effects 0.000 description 4
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000003757 reverse transcription PCR Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 108700028369 Alleles Proteins 0.000 description 3
- 208000004736 B-Cell Leukemia Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 108010052090 Renilla Luciferases Proteins 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 230000030833 cell death Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 238000007914 intraventricular administration Methods 0.000 description 3
- PGHMRUGBZOYCAA-UHFFFAOYSA-N ionomycin Natural products O1C(CC(O)C(C)C(O)C(C)C=CCC(C)CC(C)C(O)=CC(=O)C(C)CC(C)CC(CCC(O)=O)C)CCC1(C)C1OC(C)(C(C)O)CC1 PGHMRUGBZOYCAA-UHFFFAOYSA-N 0.000 description 3
- PGHMRUGBZOYCAA-ADZNBVRBSA-N ionomycin Chemical compound O1[C@H](C[C@H](O)[C@H](C)[C@H](O)[C@H](C)/C=C/C[C@@H](C)C[C@@H](C)C(/O)=C/C(=O)[C@@H](C)C[C@@H](C)C[C@@H](CCC(O)=O)C)CC[C@@]1(C)[C@@H]1O[C@](C)([C@@H](C)O)CC1 PGHMRUGBZOYCAA-ADZNBVRBSA-N 0.000 description 3
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 3
- 230000009456 molecular mechanism Effects 0.000 description 3
- 230000010399 physical interaction Effects 0.000 description 3
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000011830 transgenic mouse model Methods 0.000 description 3
- PRDFBSVERLRRMY-UHFFFAOYSA-N 2'-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-2,5'-bibenzimidazole Chemical compound C1=CC(OCC)=CC=C1C1=NC2=CC=C(C=3NC4=CC(=CC=C4N=3)N3CCN(C)CC3)C=C2N1 PRDFBSVERLRRMY-UHFFFAOYSA-N 0.000 description 2
- 239000012103 Alexa Fluor 488 Substances 0.000 description 2
- ZAINTDRBUHCDPZ-UHFFFAOYSA-M Alexa Fluor 546 Chemical compound [H+].[Na+].CC1CC(C)(C)NC(C(=C2OC3=C(C4=NC(C)(C)CC(C)C4=CC3=3)S([O-])(=O)=O)S([O-])(=O)=O)=C1C=C2C=3C(C(=C(Cl)C=1Cl)C(O)=O)=C(Cl)C=1SCC(=O)NCCCCCC(=O)ON1C(=O)CCC1=O ZAINTDRBUHCDPZ-UHFFFAOYSA-M 0.000 description 2
- 239000012114 Alexa Fluor 647 Substances 0.000 description 2
- 102100037674 Bis(5'-adenosyl)-triphosphatase Human genes 0.000 description 2
- 102000001764 CREB-Binding Protein Human genes 0.000 description 2
- 108010040163 CREB-Binding Protein Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 108090000331 Firefly luciferases Proteins 0.000 description 2
- 108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- 108010021466 Mutant Proteins Proteins 0.000 description 2
- 102000008300 Mutant Proteins Human genes 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 241000242739 Renilla Species 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 108010005713 bis(5'-adenosyl)triphosphatase Proteins 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000030570 cellular localization Effects 0.000 description 2
- 210000000805 cytoplasm Anatomy 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 230000004987 nonapoptotic effect Effects 0.000 description 2
- 230000034190 positive regulation of NF-kappaB transcription factor activity Effects 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 150000003839 salts Chemical group 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- MIJDSYMOBYNHOT-UHFFFAOYSA-N 2-(ethylamino)ethanol Chemical compound CCNCCO MIJDSYMOBYNHOT-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- 239000012099 Alexa Fluor family Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 208000016718 Chromosome Inversion Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 238000003718 Dual-Luciferase Reporter Assay System Methods 0.000 description 1
- 108700024394 Exon Proteins 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 208000034826 Genetic Predisposition to Disease Diseases 0.000 description 1
- 208000034951 Genetic Translocation Diseases 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 101001027128 Homo sapiens Fibronectin Proteins 0.000 description 1
- 101000882390 Homo sapiens Histone acetyltransferase p300 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000254158 Lampyridae Species 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 102000002576 MAP Kinase Kinase 1 Human genes 0.000 description 1
- 108010068342 MAP Kinase Kinase 1 Proteins 0.000 description 1
- 102000001291 MAP Kinase Kinase Kinase Human genes 0.000 description 1
- 108060006687 MAP kinase kinase kinase Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 101000978776 Mus musculus Neurogenic locus notch homolog protein 1 Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102000008125 NF-kappa B p52 Subunit Human genes 0.000 description 1
- 108010074852 NF-kappa B p52 Subunit Proteins 0.000 description 1
- 102000007999 Nuclear Proteins Human genes 0.000 description 1
- 108010089610 Nuclear Proteins Proteins 0.000 description 1
- 229940116355 PI3 kinase inhibitor Drugs 0.000 description 1
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 1
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 1
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000033759 Prolymphocytic T-Cell Leukemia Diseases 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010001859 Proto-Oncogene Proteins c-rel Proteins 0.000 description 1
- 102000000850 Proto-Oncogene Proteins c-rel Human genes 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 239000012979 RPMI medium Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 102220384943 c.120G>C Human genes 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000008045 co-localization Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000004624 confocal microscopy Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000006801 homologous recombination Effects 0.000 description 1
- 238000002744 homologous recombination Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- MIKKOBKEXMRYFQ-WZTVWXICSA-N meglumine amidotrizoate Chemical compound C[NH2+]C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C([O-])=O)=C1I MIKKOBKEXMRYFQ-WZTVWXICSA-N 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000005937 nuclear translocation Effects 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 102000027450 oncoproteins Human genes 0.000 description 1
- 108091008819 oncoproteins Proteins 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002935 phosphatidylinositol 3 kinase inhibitor Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001855 preneoplastic effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000010837 receptor-mediated endocytosis Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 108091006106 transcriptional activators Proteins 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 238000012250 transgenic expression Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention relates generally to the field of molecular biology. More particularly, it concerns methods for inhibiting development of mature B cell leukemia in a subject by inhibiting deregulation of Tell in cells in the subject. [0004] Certain aspects of the invention include application in diagnostics, therapeutics, and prognostics of B cell lymphocytic leukemia associated disorders.
- B-CLL B cell chronic lymphocytic leukemia
- TCLl T cell leukemia/ lymphoma 1
- B-CLL and aggressive human B-CLLs overexpress Tell, indicating that deregulation of TCLl is critically important in the pathogenesis of the aggressive form of B-CLL.
- Tell is a coactivator of the Akt oncoprotein, a critical antiapoptotic molecule in T cells. More recently, it has been reported that transgenic mice expressing constitutively active myristylated Akt in T cells develop T cell leukemias. These results suggest that Akt may be responsible for Tell -mediated lymphomagenesis in T cells. Akt could be robustly activated in mouse B cells by homozygous deletion of Pten. Surprisingly, these mice did not develop B cell malignancies, suggesting that Tell deregulation in B cells causes B-CLL by mechanisms other than Akt activation.
- NF-KB pathway in B-CLL For example, transgenic expression of a proliferation-inducing TNF ligand (APRIL), a member of the TNF superfamily involved in NF-KB activation, resulted in significant expansions of B220+CD5+ cells.
- APRIL proliferation-inducing TNF ligand
- B-CLL B cell chronic leukemia
- a method of treating a subject with a B cell chronic lymphocytic leukemia associated disease comprising: administering a therapeutically effective amount of a composition capable of inhibiting overexpression of T cell leukemia/lymphoma 1 (Tell) by one or more of: i) inhibiting the NF- KB pathway in the cells, and ii) activating activator protein 1 (AP-I) in the cells.
- Tell T cell leukemia/lymphoma 1
- API activating activator protein 1
- B-CLL B cell chronic lymphocytic leukemia
- a method of treating a B cell chronic lymphocytic leukemia (B-CLL) associated disease in a subject comprising: determining the amount of at least Tell expressed in cells in the subject, relative to control cells Tell; and altering the amount of Tell expressed in the subject by administering to the subject an effective amount of at least one compound for inhibiting expression of Tell by one or more of: i) inhibiting the NF- ⁇ B pathway in the cells, and ii) activating activator protein 1 (AP-I) in the cells, such that proliferation of the B-CLL associated disease in the subject is inhibited.
- B-CLL B cell chronic lymphocytic leukemia
- a method of assessing the effectiveness of a therapy to prevent, diagnose and/or treat a B cell chronic lymphocytic leukemia associated disease comprising: subjecting an animal to a therapy whose effectiveness is being assessed, and determining the level of effectiveness of the treatment being tested in treating or preventing a B cell chronic lymphocytic leukemia associated disease, by evaluating at least one biomarker for Tell.
- the candidate therapeutic agent comprises one or more of: pharmaceutical compositions, nutraceutical compositions, and homeopathic compositions. Also, in certain embodiments, the therapy being assessed is for use in a human subject.
- an agent that interferes with a B cell chronic lymphocytic leukemia associated disease response signaling pathway for the manufacture of a medicament for treating, preventing, reversing or limiting the severity of a B cell chronic lymphocytic leukemia associated disease complication in an individual, wherein the agent comprises at least one biomarker for Tell.
- a method of treating, preventing, reversing or limiting the severity of a B cell chronic lymphocytic leukemia associated disease complication in an individual in need thereof comprising: administering to the individual an agent that interferes with at least a B cell chronic lymphocytic leukemia associated disease response cascade, wherein the agent comprises at least one biomarker for Tell which: i) inhibits the NF- ⁇ B pathway in the cells, and/or ii) activates activator protein 1 (AP-I) expression in the cells.
- an agent that interferes with at least a B cell chronic lymphocytic leukemia associated disease response cascade
- the agent comprises at least one biomarker for Tell which: i) inhibits the NF- ⁇ B pathway in the cells, and/or ii) activates activator protein 1 (AP-I) expression in the cells.
- an agent that interferes with at least a B cell chronic lymphocytic leukemia associated disease response cascade for the manufacture of a medicament for treating, preventing, reversing or limiting the severity of a cancer-related disease complication in an individual, wherein the agent comprises at least one biomarker for Tell which: i) inhibits the NF- ⁇ B pathway in the cells, and/or ii) activates activator protein 1 (AP-I) expression in the cells.
- an antibody which binds to an epitope on Tell wherein the antibody modulates at least one of: an interaction between the epitope and activator protein 1 (AP-I).
- a pharmaceutical composition comprising such antibody.
- a method of treating a B-CLL disease state in which the activity of activator protein 1 (AP-I) is altered in a mammal comprising administering to the mammal a therapeutically effective amount of an antibody capable of binding to an epitope on a Tell protein, thereby modulating a Tell enhanced activity of the activator protein 1 (AP-I).
- a method of treating a B-CLL disease state in which the activity of activator protein 1 (AP-I) is altered in a mammal comprising: administering to the mammal a therapeutically effective amount of a peptide fragment of activator protein 1 (AP-I), wherein the peptide fragment binds to the activator protein 1 (AP-I), thereby modulating a Tell enhanced kinase activity of the activator protein 1 (AP-I).
- API activator protein 1
- a compound comprising a Tell mimic, wherein the Tell mimic binds to an activator protein 1 (AP-I) in any cell and is functionally active in mimicking a Tell enhanced activation of the activator protein 1 (AP-I).
- API activator protein 1
- a method of treating a disease state in which the activity of activator protein 1 (AP-I) is altered in a mammal comprising administering to the mammal a therapeutically effective amount of a Tell mimic, wherein the Tell mimic binds to the activator protein 1 (AP-I), thereby activating a Tell enhanced kinase activity of the activator protein 1 (AP-I).
- a compound comprising a Tell antagonist, wherein the Tell antagonist binds to activator protein 1 (AP-I) in any cell and is functionally active in modulating a Tell enhanced activation of the activator protein 1 (AP-I).
- API activator protein 1
- Figs. 1A-1C Tell activates NF- ⁇ B-dependent transcription:
- Fig. IA Chromatograms of sequences surrounding T381, E40D, R52H mutations obtained from sequencing of buccal swab constitutional DNA, B-CLL DNA, and results of RT-PCR (for T381 mutant) using RNA from B-CLL cells.
- Fig. IB Tell activates NF- ⁇ B.
- NIH 3T3 cells were cotransfected with 50 ng of pNF-kB-Luc reporter and 50 ng of pRL-TK Renilla reporter constructs.
- 1.5 ⁇ g of CMV5-empty vector, or a combination of 0.75 ⁇ g of CMV5-empty vector and 0.75 ⁇ g of CMV5-Tcll WT, or CMV5-Tcll T381 constructs were used.
- Five nanograms of pFC- MEKK were added where indicated.
- Cells were treated with 200 nmol/L of Wortmannin overnight, where indicated.
- the normalized promoter activity of pNF-kB-Luc in NIH 3T3 cells transfected with CMV5-empty vector was set as 1.
- Fig. 1C Tell interacts with p300.
- Upper Some 293 cells were cotransfected with p300-HA and Omni-Fhit or p300-HA and Omni-Tcll constructs. After lysis, immunoprecipitations were carried out with anti-HA, IgG, or anti-omni antibodies. Western blot analysis was carried out as indicated.
- Daudi cells were lysed and immunoprecipitations were carried out with anti-Tcll antibody, IgG, or anti-p300 antibody. Unlabeled higher band in the Tell panel represents IgG. Western blot analysis was carried out as indicated.
- Figs. 2A-2G Tell inhibits AP-I activity:
- Fig. 2A Some 293 cells were cotransfected with 500 ng of pAP-1-Luc reporter and 50 ng of pRL-TK Renilla reporter constructs. In addition, 1.5 ⁇ g of CMV5-empty vector, CMV5-TcllWT, or mutant constructs and 2.5 ng of pFC-MEKK (where indicated) were used. Cells were treated with 200 nmol/L of Wortmannin overnight, where indicated. The normalized promoter activity of pAP-1-Luc in HEK293 cells transfected with CMV5- empty vector was set as 1.
- Fig. 2B Same as in Fig. 2A, except instead of pFC-MEKK construct, 5 ng of c-
- Fos-V5, c-Jun, JunB, or combinations of 5 ng of c-Fos-V5 and S ng of c-Jun or JunB were added, as indicated.
- Fig. 2C Some 293 cells were cotransfected with c-Fos-V5 and CMV5-Tcll WT or c-Fos-V5 and CMV5-Tcll T381 constructs. After lysis, immunoprecipitations were carried out with anti-c-Fos, IgG, or anti-Tcll antibodies. Western blot analysis was carried out as indicated.
- Figs. 2D-2F Some 293 cells were cotransfected with myc-Tcll T381 or myc-Fhit with c-Fos-V5 (Fig. 2D), c-Jun-HA (Fig. 2E), or JunB (Fig. 2F), as indicated. After lysis, immunoprecipitations were carried out with anti-myc, IgG, and anti-c-Fos (Fig. 2D), anti-HA (Fig. 2E), and anti-JunB (Fig. 2F) antibodies as indicated. Western blot analysis was carried out with the indicated antibodies. [0036] Fig.
- FIG. 2G Some 293 cells were transfected with myc-Tcll and treated with 50 ng/mL PMA and 1 ⁇ g/mL ionomycin to increase endogenous c-Jun expression, 2 h before lysis. Immunoprecipitations were carried out with anti-c-Jun, IgG, or anti-myc antibodies.
- Fig. 2H Daudi cells were treated with 50 ng/mL PMA and 1 ⁇ g/mL ionomycin 2 h before lysis. Immunoprecipitations were carried out with anti-Tcll, IgG, or anti-c-Jun antibodies.
- Fig. 2H Daudi cells were treated with 50 ng/mL PMA and 1 ⁇ g/mL ionomycin 2 h before lysis. Immunoprecipitations were carried out with anti-Tcll, IgG, or anti-c-Jun antibodies.
- Figs. 4A-4 Tell inhibits MEKKl -mediated cell death:
- Fig. 4A Some 293 cells were transfected with 1.5 ⁇ g of pCMV5 -empty vector
- Figs. 4B-4C Some 293 cells were transfected with 1.5 ⁇ g of pCMV5-empty vector, or 0.5 ⁇ g of pFC-MEKK and 1 ⁇ g of pCMV5-empty or pCMV5-Tcll WT constructs.
- Fig. 4B Percentage of apoptotic cells. For each transfection at least 20 fields were selected for counting the percentage of dead cells (indicated by fragmented nucleus).
- Fig. 4C Results of the same experiment were visualized by using confocal microscopy.
- B cell chronic lymphocytic leukemia (B-CLL) is the most common human leukemia.
- TCLl T cell leukemia/lymphoma 1
- A-I activator protein 1
- Tell physically interacts with c-Jun, JunB, and c-Fos and inhibits AP-I transcriptional activity. Additionally, Tell activates NF- ⁇ B by physically interacting with p30O/CREB binding protein.
- TCLl gene was sequenced in 600 B-CLL samples and 2 heterozygous mutations were found: T38I and R52H. It is to be noted that both mutants showed gain of function as AP-I inhibitors. The results indicate that Tell overexpression causes B-CLL by directly enhancing NF- ⁇ B activity and inhibiting AP-I.
- B-CLL-specific gain-of-function Tell mutants were developed.
- the TCLl gene in 600 B-CLL samples was sequenced. Sequencing analysis of all coding TCLl exons resulted in the identification of 2 heterozygous mutations resulting in amino acid substitutions, T38I and R52H (Fig. IA).
- Fig. IA The R52H mutation was also present in the matched normal buccal swab DNA (Fig. IA Right), showing a constitutional variation.
- the RT-PCR results showed that the T38I mutant TCLl mRNA was the major expressed allele in the B-CLL of origin, accounting for 80% of the TCLl mRNA, and the R52H allele was the only allele expressed (Fig. IA).
- KB a system based on the ability of mitogen-activated protein kinase kinase 1 (MEKKl) was used to activate an NF-KB reporter construct, pNF- ⁇ B-Luc expressing luciferase under the control of an NF- ⁇ B-responsive element.
- MEKKl mitogen-activated protein kinase kinase 1
- NIH 3T3 cells were transfected with the constructs indicated in Fig. IB.
- Fig. IB shows that Tclll activated NF- ⁇ B activity about 4-fold (50 versus 13), whereas the 2 mutants activated activity 2- to 3-fold.
- Fig. IB shows that wortmannin did not affect the ability of Tell to activate NF-
- the transcriptional activator CREB binding protein/p300 is a ubiquitous nuclear transcription factor involved in transactivation mediated by several signaling pathways, including the NF- ⁇ B pathway. Because p300 is a coactivator of NF- ⁇ B, the inventors herein investigated whether Tell interacts with p300. First, coimmunoprecipitation experiments were carried out, cotransfecting tagged Tell and p300 constructs into 293 cells.
- Fig. lC-Upper shows that p300 was coimmunoprecipitated with Tell
- Fig. lC-Lower shows that p300 was detected in Tell immune complexes
- Tell was coimmunoprecipitated with p300. This shows that Tell induces NF- ⁇ B-dependent transcription by interacting with p300, perhaps changing its conformation and enhancing its ability to function as an NF- ⁇ B coactivator.
- a system based on the ability of MEKKl was used to activate an AP-I reporter construct, pAP-1-Luc, expressing luciferase under the control of an AP-I- responsive element.
- Some 293 cells were transfected with the constructs indicated in Figs. 2A-2H.
- the inventors herein also investigated whether Tell WT and mutants inhibit the activity of endogenous AP-I in 293 cells. The 293 cells were transfected with MEKKl to activate AP-I.
- Fig. 2A shows that AP-I activity was induced 652-fold by MEKKl.
- Tell expression inhibited AP-I dependent transactivation ⁇ 2.5-fold, whereas Tell T38I caused a dramatic ⁇ 100-fold inhibition (652 versus 6.3).
- the R52H mutant also showed a more potent effect compared with WT Tell (176 versus 287, compared with 652). Similar results were obtained with cells treated with wortmannin (Fig. 2A).
- Tell expression inhibited AP-I- dependent transactivation -2.5-fold, whereas the T38I mutant caused 150-fold inhibition (981 versus 6.5).
- Akt To determine whether Tell inhibits individual components of the AP-I complex, similar experiments were carried out using WT Tell and the T38I mutant. AP-I was activated by overexpression of single AP-I components rather than by using MEKKl.
- Fig. 2B-Left shows that Tell inhibits separately c-Fos, c-Jun, and Jun-B, whereas
- Figs. 2C-2F show results of these experiments using transiently expressed proteins.
- T38I mutant protein showed much robust coimmunoprecipitation with c-Fos than WT Tell (Fig. 2C-Lower vs. Fig. 2C-Upper), suggesting a relation with its more potent inhibition of AP-I compared with WT Tell.
- the specificity of this interaction is shown in Fig.
- Fig. 2G shows that endogenous c-Jun coimmunoprecipitated with transfected Tell in 293 cells, whereas Tell was detected in immune complexes of endogenous c-Jun.
- Physical interaction of endogenous Tell and c-Jun in Daudi cells is shown in Fig. 2H.
- Tell was present in immune complexes of endogenous c-Jun, and c-Jun was coimmunoprecipitated with Tell.
- Fig. 2G and Fig. 2H because c-Jun is expressed at very low levels, cells were pretreated with phorbol 12-myristate 13-acetate (PMA) and ionomycin.
- PMA phorbol 12-myristate 13-acetate
- Tell induces NF-KB-dependent transcription and represses AP-I -dependent transcription by participating directly in transcriptional complexes (Fig. 1 and Fig. 2); as such, the inventors herein now believe that these actions of Tell will result in cell death inhibition.
- MEKKl induces apoptosis in 293 cells by c-jun N-terminal kinase (JNK) and AP-I activation, the inventors used the construct expressing the kinase domain of MEKKl that was used to induce AP-I in Fig. 2.
- Figs. 4A-C show that Tell indeed inhibits AP-1-mediated apoptosis in 293 cells.
- PARPl poly(ADP-ribose) polymerase 1
- Tell functions as an AP-I inhibitor, thus providing important insights concerning molecular mechanisms involved in B-CLL development. The importance of these results is greatly enhanced by the fact that the somatic T38I mutant showed gain-of-function properties.
- the R52H mutation was present in constitutional DNA of the same patient and also led to gain of function in AP-I inhibition. While not wishing to be bound by theory, the inventors herein believe that this change represents a rare polymorphism causing genetic predisposition to B-CLL.
- the physical interaction between Tell and transcription factors such as p300 and AP-I components provides a novel molecular mechanism of Tell function and proves that this function of Tell is independent of Akt.
- Tell has other functions (for example, as a transporter).
- NF-KB or activate AP-I may be useful in treatment of the aggressive form of B-CLL.
- a total of 600 B-CLL samples were obtained after informed consent from patients diagnosed with B-CLL from the CLL Research Consortium. Research was performed with the approval of the Institutional Review Board of Ohio State University. Briefly, blood was obtained from CLL patients, and lymphocytes were isolated through Ficoll/Hypaque gradient centrifugation (Amersham) and processed for RNA extraction by using the standard TRlzol method.
- Oligonucleotides used in genomic DNA PCR and sequencing were:
- TCL1_149F 5'-CATGCTGCCCGGATATAAAG-S' [SEQ ID NO: I];
- TCL1_539R 5'-TGCCTGGAGAACTCCTATTCAT-S' [SEQ ID NO: 2];
- TCL13 1 F 5'- GAAGTGAGCTTCAGGGAACAGT-S'; [SEQ ID NO: 3];
- Oligonucleotides used in RT-PCR and sequencing were:
- TCL1D5 5'- CCTGTGGGCCTGGGAGAAGT-3' [SEQ ID NO: 5] and
- TCL1R5 5'-TCCTCCACGCCGTCAATCTT-S' [SEQ ID NO: 6].
- WT and mutant TCLl and FHIT ORFs were cloned into the pCMV-2xMyc vector, modified from the pCMV-Myc vector (BD Biosciences) with an added Myc tag, creating Myc tags at both 5' and 3' termini.
- the resulting constructs were named 2xMyc-Tcll WT, 2xMyc-Tcll T381, and 2xMyc-Fhit.
- c-Jun-HA was constructed by inserting the c-Jun ORF into the pCMV-HA vector (BD Biosciences).
- the c-Fos-V5 construct was purchased from Invitrogen.
- the p300-HA construct was purchased from Upstate Biotechnology.
- the Akt- HA construct has been described previously (Pekarsky Y., et al. (2000) Tell enhances Akt kinase activity and mediates its nuclear translocation; Proc Nat/ Acad Sci USA 97:3028- 3033).
- the Dual-luciferase Reporter Assay System and Renilla luciferase reporter vector pRL-TK were purchased from Promega.
- the AP-I reporter construct, pAPl-Luc, NF-KB reporter construct, pNF-kB-Luc and the construct encoding the kinase domain of MEKKl under control of the CMV promoter, pFC-MEKK, were purchased from Stratagene.
- NIH 3T3 and 293 cells were grown in RPMI medium 1640 with 10% FBS and lOO.sg/L gentamicin at 37 0 C.
- FuGene 6 transfection reagent and protease inhibitor mixture tablets were obtained from Roche.
- Transfections, except luciferase assay experiments, cell lysate preparations, and Western blot analysis were carried out. Immunoblots were developed by using Pierce ECL Western blot analysis substrate or SuperSignal West Femto Maximum Sensitivity Substrate from Thermo Scientific.
- Antibodies used were: anti-Tcll (sc-32331 for Western blot analysis and immunoprecipitation with p300; sc-11156 and sell 155 for immunoprecipitation with c-Jun), anti-Omni (sc-7270 for immunoprecipitation and Western blot analysis; sc-499 for immunofluorescence), anti-p300 (sc-32244), anti-Myc (9E10), anti-Myc-HRP (9E10), anti-c-Jun (sc-1694 for immunoprecipitation), anti-Jung (sc- 8051 for immunoprecipitation; sc-46 for Western blot analysis), anti-c-Fos (sc-447 for immunoprecipitation and immunofluorescence) (Santa Cruz Biotechnology), anti-c-Jun (610326 for Western blot analysis, BD Biosciences), anti-HA (HA.1 1) (Covance), anti-V5- HRP (Invitrogen), rat anti-HA (
- HEK293 cells were grown on human fibronectin Cellware 2- well culture slides
- Immunofluorescence experiments were carried out with a Zeiss LCM 510 confocal microscope. Secondary antibodies used for immunofluorescence were as follows: goat anti-mouse Alexa Fluor 546 (red), goat anti-rat Alexa Fluor 647 (far-red), and goat anti- rabbit Alexa Fluor 488 (green), all purchased from Invitrogen.
- NIH 3T3 or 293 cells were transfected with the indicated constructs. Firefly and renilla luciferase activities were assayed with the dual luciferase assay system (Promega), and firefly luciferase activity was normalized to renilla luciferase activity, as suggested by the manufacturer. All experiments were carried out in triplicate and repeated 3 times with consistent results.
- Apoptosis was assessed by scoring the number of cells displaying fragmented nuclei, stained with 10.sg/mL of Hoechst 33342 (Invitrogen). An alternative method of apoptosis detection was also used.
- HEK 293 cells were transfected with either 1.5 ⁇ g of pCMV5-empty vector or 0.5 ⁇ g of pFC-MEKK with l ⁇ g of pCMV5-empty or pCMV5-Tcll WT or pCMV5-Tcll T381 constructs. Twenty-four hours later both dead and live cells were collected and lysed. These lysates were probed with anti-PARPl antibody (556362; BD Biosciences). The 116-kDa intact form of PARPl was present in both nonapoptotic and apoptotic cells. The 85-kDa PARPl cleavage fragment was present only in apoptotic cells.
- the invention provides methods of treatment and prophylaxis by administration to a subject an effective amount of a therapeutic, i.e., a monoclonal (or polyclonal) antibody, viral vector, Tell mimic or Tell antagonist of the present invention.
- a therapeutic i.e., a monoclonal (or polyclonal) antibody, viral vector, Tell mimic or Tell antagonist of the present invention.
- the therapeutic is substantially purified.
- the subject is preferably an animal, including but not limited to, animals such as cows, pigs, chickens, etc., and is preferably a mammal, and most preferably human.
- a therapeutic of the invention e.g., encapsulation in liposomes, microparticles, microcapsules, expression by recombinant cells, receptor-mediated endocytosis, construction of a therapeutic nucleic acid as part of a retroviral or other vector, etc.
- Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes.
- the compounds are administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local.
- compositions of the invention may be desirable to administer locally to the area in need of treatment; this may be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, the implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
- administration is by direct injection at the site (or former site) of a malignant tumor or neoplastic or pre-neoplastic tissue.
- the nucleic acid is administered in vivo to promote expression of its encoded protein, by constructing it as part of an appropriate nucleic acid expression vector and administering it so that it becomes intracellular, or coating with lipids or cell-surface receptors or transfecting agents, or by administering it in linkage to a homeobox-like peptide which is known to enter the nucleus.
- a nucleic acid therapeutic can be introduced intracellularly and incorporated within host cell DNA for expression, by homologous recombination.
- compositions comprise a therapeutically effective amount of a therapeutic, and a pharmaceutically acceptable carrier or excipient.
- a pharmaceutically acceptable carrier includes, but is not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof.
- the carrier and composition can be sterile. The formulation will suit the mode of administration.
- the composition can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
- the composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
- the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
- Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
- the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings.
- compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
- the composition also includes a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection.
- the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
- composition is to be administered by infusion, it is be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
- an ampoule of sterile water for injection or saline is provided so that the ingredients are mixed prior to administration.
- the therapeutics of the invention are formulated as neutral or salt forms.
- Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.
- the amount of the therapeutic of the invention which will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and is determined by standard clinical techniques.
- in vitro assays may optionally be employed to help identify optimal dosage ranges.
- the precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and is decided according to the judgment of the practitioner and each patient's circumstances.
- suitable dosage ranges for intravenous administration are generally about 20-500 micrograms of active compound per kilogram body weight.
- Suitable dosage ranges for intranasal administration are generally about 0.01 pg/kg body weight to 1 mg/kg body weight.
- Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems
- the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
- a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP09828195A EP2352524A1 (fr) | 2008-11-21 | 2009-11-19 | Cellule t11 en tant que régulateur transcriptionnel |
US13/129,881 US20110311555A1 (en) | 2008-11-21 | 2009-11-19 | Tc11 as a Transcriptional Regulator |
CN2009801530248A CN102271706A (zh) | 2008-11-21 | 2009-11-19 | 作为转录调节剂的Tcl1 |
CA2744326A CA2744326A1 (fr) | 2008-11-21 | 2009-11-19 | Cellule t11 en tant que regulateur transcriptionnel |
JP2011537606A JP2012509886A (ja) | 2008-11-21 | 2009-11-19 | 転写制御因子としてのTcl1 |
AU2009316584A AU2009316584A1 (en) | 2008-11-21 | 2009-11-19 | Tcl1 as a transcriptional regulator |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11678608P | 2008-11-21 | 2008-11-21 | |
US61/116,786 | 2008-11-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2010059779A1 true WO2010059779A1 (fr) | 2010-05-27 |
Family
ID=42198493
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2009/065072 WO2010059779A1 (fr) | 2008-11-21 | 2009-11-19 | Cellule t11 en tant que régulateur transcriptionnel |
Country Status (7)
Country | Link |
---|---|
US (1) | US20110311555A1 (fr) |
EP (1) | EP2352524A1 (fr) |
JP (1) | JP2012509886A (fr) |
CN (1) | CN102271706A (fr) |
AU (1) | AU2009316584A1 (fr) |
CA (1) | CA2744326A1 (fr) |
WO (1) | WO2010059779A1 (fr) |
Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7943318B2 (en) | 2006-01-05 | 2011-05-17 | The Ohio State University Research Foundation | Microrna-based methods and compositions for the diagnosis, prognosis and treatment of lung cancer |
US7985584B2 (en) | 2006-03-20 | 2011-07-26 | The Ohio State University Research Foundation | MicroRNA fingerprints during human megakaryocytopoiesis |
US8034560B2 (en) | 2007-01-31 | 2011-10-11 | The Ohio State University Research Foundation | MicroRNA-based methods and compositions for the diagnosis, prognosis and treatment of acute myeloid leukemia (AML) |
US8053186B2 (en) | 2007-06-15 | 2011-11-08 | The Ohio State University Research Foundation | Oncogenic ALL-1 fusion proteins for targeting Drosha-mediated microRNA processing |
US8071292B2 (en) | 2006-09-19 | 2011-12-06 | The Ohio State University Research Foundation | Leukemia diagnostic methods |
US8084199B2 (en) | 2006-07-13 | 2011-12-27 | The Ohio State University Research Foundation | Method of diagnosing poor survival prognosis colon cancer using microRNA-21 |
US8252538B2 (en) | 2006-11-01 | 2012-08-28 | The Ohio State University | MicroRNA expression signature for predicting survival and metastases in hepatocellular carcinoma |
US8367632B2 (en) | 2007-07-31 | 2013-02-05 | Ohio State University Research Foundation | Methods for reverting methylation by targeting methyltransferases |
US8389210B2 (en) | 2006-01-05 | 2013-03-05 | The Ohio State University Research Foundation | MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors |
US8465917B2 (en) | 2007-06-08 | 2013-06-18 | The Ohio State University Research Foundation | Methods for determining heptocellular carcinoma subtype and detecting hepatic cancer stem cells |
US8466119B2 (en) | 2007-08-22 | 2013-06-18 | The Ohio State University Research Foundation | Methods and compositions for inducing deregulation of EPHA7 and ERK phosphorylation in human acute leukemias |
US8658370B2 (en) | 2005-08-01 | 2014-02-25 | The Ohio State University Research Foundation | MicroRNA-based methods and compositions for the diagnosis, prognosis and treatment of breast cancer |
US8664192B2 (en) | 2011-03-07 | 2014-03-04 | The Ohio State University | Mutator activity induced by microRNA-155 (miR-155) links inflammation and cancer |
US8859202B2 (en) | 2012-01-20 | 2014-10-14 | The Ohio State University | Breast cancer biomarker signatures for invasiveness and prognosis |
US8911998B2 (en) | 2007-10-26 | 2014-12-16 | The Ohio State University | Methods for identifying fragile histidine triad (FHIT) interaction and uses thereof |
US8916533B2 (en) | 2009-11-23 | 2014-12-23 | The Ohio State University | Materials and methods useful for affecting tumor cell growth, migration and invasion |
US8946187B2 (en) | 2010-11-12 | 2015-02-03 | The Ohio State University | Materials and methods related to microRNA-21, mismatch repair, and colorectal cancer |
US9085804B2 (en) | 2007-08-03 | 2015-07-21 | The Ohio State University Research Foundation | Ultraconserved regions encoding ncRNAs |
US9125923B2 (en) | 2008-06-11 | 2015-09-08 | The Ohio State University | Use of MiR-26 family as a predictive marker for hepatocellular carcinoma and responsiveness to therapy |
US9249468B2 (en) | 2011-10-14 | 2016-02-02 | The Ohio State University | Methods and materials related to ovarian cancer |
US9481885B2 (en) | 2011-12-13 | 2016-11-01 | Ohio State Innovation Foundation | Methods and compositions related to miR-21 and miR-29a, exosome inhibition, and cancer metastasis |
US10758619B2 (en) | 2010-11-15 | 2020-09-01 | The Ohio State University | Controlled release mucoadhesive systems |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2484782B1 (fr) | 2006-01-05 | 2015-11-18 | The Ohio State University Research Foundation | Procédés à base de micro ARN et compositions pour le diagnostic et le traitement des cancers solides |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20010026796A1 (en) * | 2000-03-14 | 2001-10-04 | Croce Carlo M. | TCL1 enhances Akt kinase activity and mediates its nuclear translocation |
US20060127895A1 (en) * | 2001-12-03 | 2006-06-15 | Kanaga Sabapathy | Use of c-jun or c-jun activating agents such as uv or c-jun n-terminal kinases (junks) for treating cancer |
US20060188924A1 (en) * | 1994-10-27 | 2006-08-24 | Giandomenico Russo | TCL-1 gene and protein and related methods and compositions |
US20060247448A1 (en) * | 2002-03-08 | 2006-11-02 | Eisai Co., Ltd. | Macrocyclic compounds useful as pharmaceuticals |
-
2009
- 2009-11-19 CN CN2009801530248A patent/CN102271706A/zh active Pending
- 2009-11-19 WO PCT/US2009/065072 patent/WO2010059779A1/fr active Application Filing
- 2009-11-19 CA CA2744326A patent/CA2744326A1/fr not_active Abandoned
- 2009-11-19 JP JP2011537606A patent/JP2012509886A/ja active Pending
- 2009-11-19 EP EP09828195A patent/EP2352524A1/fr not_active Withdrawn
- 2009-11-19 AU AU2009316584A patent/AU2009316584A1/en not_active Abandoned
- 2009-11-19 US US13/129,881 patent/US20110311555A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060188924A1 (en) * | 1994-10-27 | 2006-08-24 | Giandomenico Russo | TCL-1 gene and protein and related methods and compositions |
US20010026796A1 (en) * | 2000-03-14 | 2001-10-04 | Croce Carlo M. | TCL1 enhances Akt kinase activity and mediates its nuclear translocation |
US20060127895A1 (en) * | 2001-12-03 | 2006-06-15 | Kanaga Sabapathy | Use of c-jun or c-jun activating agents such as uv or c-jun n-terminal kinases (junks) for treating cancer |
US20060247448A1 (en) * | 2002-03-08 | 2006-11-02 | Eisai Co., Ltd. | Macrocyclic compounds useful as pharmaceuticals |
Non-Patent Citations (3)
Title |
---|
BICHI ET AL.: "Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression", PNAS, vol. 99, no. 10, 14 May 2002 (2002-05-14), USA, pages 6955 - 6960, XP003024737 * |
HIROMURA ET AL.: "Identification of Nerve Growth Factor-responsive Element of the TCL1 Promoter as a Novel Negative Regulatory Element'", JBC, vol. 281, no. 38, 22 September 2006 (2006-09-22), pages 27753 - 27764, XP008148323 * |
PEKARSKY ET AL.: "Animal Models for Chronic Lymphocytic Leukemia.", JOURNAL OF CELLULAR BIOCHEMISTRY, vol. 100, 2007, pages 1109 - 1118, XP008114993 * |
Cited By (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8658370B2 (en) | 2005-08-01 | 2014-02-25 | The Ohio State University Research Foundation | MicroRNA-based methods and compositions for the diagnosis, prognosis and treatment of breast cancer |
US8377637B2 (en) | 2006-01-05 | 2013-02-19 | The Ohio State University Research Foundation | MicroRNA-based methods and compositions for the diagnosis, prognosis and treatment of lung cancer using miR-17-3P |
US7943318B2 (en) | 2006-01-05 | 2011-05-17 | The Ohio State University Research Foundation | Microrna-based methods and compositions for the diagnosis, prognosis and treatment of lung cancer |
US8361710B2 (en) | 2006-01-05 | 2013-01-29 | The Ohio State University Research Foundation | MicroRNA-based methods and compositions for the diagnosis, prognosis and treatment of lung cancer using miR-21 |
US8389210B2 (en) | 2006-01-05 | 2013-03-05 | The Ohio State University Research Foundation | MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors |
US7985584B2 (en) | 2006-03-20 | 2011-07-26 | The Ohio State University Research Foundation | MicroRNA fingerprints during human megakaryocytopoiesis |
US8354224B2 (en) | 2006-03-20 | 2013-01-15 | The Ohio State University | MicroRNA fingerprints during human megakaryocytopoiesis |
US8084199B2 (en) | 2006-07-13 | 2011-12-27 | The Ohio State University Research Foundation | Method of diagnosing poor survival prognosis colon cancer using microRNA-21 |
US8071292B2 (en) | 2006-09-19 | 2011-12-06 | The Ohio State University Research Foundation | Leukemia diagnostic methods |
US8252538B2 (en) | 2006-11-01 | 2012-08-28 | The Ohio State University | MicroRNA expression signature for predicting survival and metastases in hepatocellular carcinoma |
US8034560B2 (en) | 2007-01-31 | 2011-10-11 | The Ohio State University Research Foundation | MicroRNA-based methods and compositions for the diagnosis, prognosis and treatment of acute myeloid leukemia (AML) |
US8465917B2 (en) | 2007-06-08 | 2013-06-18 | The Ohio State University Research Foundation | Methods for determining heptocellular carcinoma subtype and detecting hepatic cancer stem cells |
US8349560B2 (en) | 2007-06-15 | 2013-01-08 | The Ohio State University Research | Method for diagnosing acute lymphomic leukemia (ALL) using miR-222 |
US8361722B2 (en) | 2007-06-15 | 2013-01-29 | The Ohio State University Research Foundation | Method for diagnosing acute lymphomic leukemia (ALL) using miR-221 |
US8053186B2 (en) | 2007-06-15 | 2011-11-08 | The Ohio State University Research Foundation | Oncogenic ALL-1 fusion proteins for targeting Drosha-mediated microRNA processing |
US8367632B2 (en) | 2007-07-31 | 2013-02-05 | Ohio State University Research Foundation | Methods for reverting methylation by targeting methyltransferases |
US9085804B2 (en) | 2007-08-03 | 2015-07-21 | The Ohio State University Research Foundation | Ultraconserved regions encoding ncRNAs |
US8466119B2 (en) | 2007-08-22 | 2013-06-18 | The Ohio State University Research Foundation | Methods and compositions for inducing deregulation of EPHA7 and ERK phosphorylation in human acute leukemias |
US8911998B2 (en) | 2007-10-26 | 2014-12-16 | The Ohio State University | Methods for identifying fragile histidine triad (FHIT) interaction and uses thereof |
US9125923B2 (en) | 2008-06-11 | 2015-09-08 | The Ohio State University | Use of MiR-26 family as a predictive marker for hepatocellular carcinoma and responsiveness to therapy |
US8916533B2 (en) | 2009-11-23 | 2014-12-23 | The Ohio State University | Materials and methods useful for affecting tumor cell growth, migration and invasion |
US8946187B2 (en) | 2010-11-12 | 2015-02-03 | The Ohio State University | Materials and methods related to microRNA-21, mismatch repair, and colorectal cancer |
US10758619B2 (en) | 2010-11-15 | 2020-09-01 | The Ohio State University | Controlled release mucoadhesive systems |
US11679157B2 (en) | 2010-11-15 | 2023-06-20 | The Ohio State University | Controlled release mucoadhesive systems |
US8664192B2 (en) | 2011-03-07 | 2014-03-04 | The Ohio State University | Mutator activity induced by microRNA-155 (miR-155) links inflammation and cancer |
US9249468B2 (en) | 2011-10-14 | 2016-02-02 | The Ohio State University | Methods and materials related to ovarian cancer |
US9481885B2 (en) | 2011-12-13 | 2016-11-01 | Ohio State Innovation Foundation | Methods and compositions related to miR-21 and miR-29a, exosome inhibition, and cancer metastasis |
US9434995B2 (en) | 2012-01-20 | 2016-09-06 | The Ohio State University | Breast cancer biomarker signatures for invasiveness and prognosis |
US8859202B2 (en) | 2012-01-20 | 2014-10-14 | The Ohio State University | Breast cancer biomarker signatures for invasiveness and prognosis |
Also Published As
Publication number | Publication date |
---|---|
CN102271706A (zh) | 2011-12-07 |
JP2012509886A (ja) | 2012-04-26 |
US20110311555A1 (en) | 2011-12-22 |
EP2352524A1 (fr) | 2011-08-10 |
CA2744326A1 (fr) | 2010-05-27 |
AU2009316584A1 (en) | 2010-05-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20110311555A1 (en) | Tc11 as a Transcriptional Regulator | |
Geffers et al. | Divergent functions and distinct localization of the Notch ligands DLL1 and DLL3 in vivo | |
Srivastava et al. | Bcl-2–mediated drug resistance: Inhibition of apoptosis by blocking nuclear factor of activated T lymphocytes (NFAT)-induced Fas ligand transcription | |
CA2273821C (fr) | Detection et modulation d'inhibiteurs de proteines d'apoptose (iap) et de polypeptides anti-apoptotiques apparentes (miap) permettant d'effectuer le diagnostic et le traitement demaladies proliferatives | |
JP5628807B2 (ja) | リジルtRNA合成酵素の細胞内水準を調節して癌転移又は癌細胞の移動を調節する方法 | |
Chin et al. | The liver-enriched transcription factor CREB-H is a growth suppressor protein underexpressed in hepatocellular carcinoma | |
JP2008505307A (ja) | HAUSP−Mdm2相互作用及びその使用 | |
Xu et al. | TRB3 interacts with CtIP and is overexpressed in certain cancers | |
Meng et al. | Imbalanced Rab3D versus Rab27 increases cathepsin S secretion from lacrimal acini in a mouse model of Sjögren's Syndrome | |
JP2002540814A (ja) | 転移性前立腺腫瘍の診断および処置のための方法 | |
Bakiri et al. | Role of heterodimerization of c-Fos and Fra1 proteins in osteoclast differentiation | |
JP2005040137A (ja) | Jnkを標的化することによりプログラム細胞死またはアポトーシスをブロックする新規な因子の同定 | |
Jones et al. | EGF receptor downregulation depends on a trafficking motif in the distal tyrosine kinase domain | |
US20110064704A1 (en) | Ship-deficiency to increase megakaryocyte and platelet production | |
Panfili et al. | The catalytic inhibitor epacadostat can affect the non-enzymatic function of IDO1 | |
Winter et al. | Co-deletion of ATAD1 with PTEN primes cells for BIM-mediated apoptosis | |
US7160681B2 (en) | Method for regulating cell growth and assays related thereto | |
US8722637B2 (en) | Methods and compositions of IG20 and DENN-SV splice variants | |
MXPA05010312A (es) | Proteinas activadoras de elementos de respuesta de amp ciclico y usos relacionados a ellas. | |
US20020160002A1 (en) | Tumor suppressor gene | |
Zhao et al. | The Regulatory Network of CREB3L1 and Its Roles in Physiological and Pathological Conditions | |
EP2021471B1 (fr) | Procédé de criblage | |
US7462447B2 (en) | Methods for evaluating susceptibility to a bone homeostasis disorder | |
US20230272479A1 (en) | Biomarker based patient selection for proteasome inhibitor treatment | |
JP2002503466A (ja) | 網膜芽細胞腫タンパク質複合体および網膜芽細胞腫相互作用タンパク質 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200980153024.8 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09828195 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2744326 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009316584 Country of ref document: AU |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011537606 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009828195 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2009316584 Country of ref document: AU Date of ref document: 20091119 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13129881 Country of ref document: US |