WO2010066891A2 - Method for predicting the response to treatment by tyrosine kinase inhibitors targeting the bcr-abl fusion protein in chronic myeloid leukaemia patients - Google Patents

Abstract

The present invention relates to a method for determining if an individual suffering from chronic myeloid leukemia (CML) is at risk of developing resistance to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein or if the individual is likely to respond to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein, comprising: a) determining the expression level of at least one of the genes selected from the group consisting of : RAD51 -like 1 (S. cerevisiae), Aurora kinase B, and Phosphatase and tensin homolog (mutated in multiple advanced cancers 1); in cells of the individual suffering from CML; b) comparing the determined expression level for each gene respectively to a predetermined reference expression level; c) deducing therefrom if the individual suffering from CML is at risk of developing resistance to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein or if the individual is likely to respond to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein.

Description

Method for predicting the response to treatment by tyrosine kinase inhibitors targeting the BCR-ABL fusion protein in chronic myeloid leukaemia patients

Field of the invention

The present invention relates to a method for determining if an individual suffering from chronic myeloid leukemia (CML) is at risk of developing a resistance to a treatment with a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein, in particular imatinib.

Background of the invention

Chronic myeloid leukaemia (CML) has an incidence of about 1/100 000 individuals. It is estimated that 20 000 new cases are detected each in Europe and in the U.S.A. CML was the first human cancer identified as being linked to an acquired chromosomal abnormality, subsequently shown to be a reciprocal translocation between chromosomes 9 and 22, notably yielding the Philadelphia (Ph) chromosome, which corresponds to the shortened chromosome 22. The resulting fusion gene product, BCR-ABL, was identified as the causative agent of the disease. BCR-ABL presents a constitutive tyrosine kinase activity which increases proliferation and survival of myeloid progenitor cells.

Imatinib (Glivec®), a potent and selective inhibitor of BCR-ABL, induces durable cytogenetic responses in the majority of Chronic myeloid leukemia (CML) patients who receive the drug early in chronic phase (CP) (Drucker et al. (2006) N Engl J Med 355:2408-2417, de Lavallade et al. (2008) J Clin Oncol 26:3358-3363). It has been shown that imatinib has the highest rate of complete cytogenetic response (CCR) among the current drugs used in the management of CML, such as IFN-α.

However, an appreciable minority (5 to 10 %) of patients fail to achieve any degree of cytogenetic response to imatinib. This is commonly referred as up-front or primary cytogenetic resistance and its incidence seems to be consistent in different patient groups. Though the clinical heterogeneity of CML has been acknowledged at the diagnosis level for more than 20 years (Sokal et al. (1985) Blood 66:1352-1357), and such heterogeneity could in part explain primary resistance to imatinib.

Accordingly, there is a need to identify CML patients unlikely to respond to imatinib at the time of diagnosis of the disease, so as to direct the patient to the most adequate treatment and to avoid prescribing unnecessary imatinib at high costs.

Two studies (Frank et al. (2006) Leukemia 20:1400-1407, Villuendas et al.

(2006) Leukemia 20:1047-1054) tried to identify the profile of the imatinib resistance gene expression in chronic CML. However, none of these studies could be validated in an independent dataset, as such their results have little clinical use.

Summary of the invention

The present invention arises from the identification, by the inventors, of a set of genes differentially expressed between CML patients resistant to imatinib, i.e. patients who fail to achieve any degree of cytogenetic response under imatinib treatment, and patients achieving complete cytogenetic response under imatinib treatment. The results were validated in two independent previously published datasets.

The present invention thus relates to a first method, preferably an in vitro method, for determining if an individual suffering from chronic myeloid leukemia (CML) is at risk of developing resistance to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein or if the individual is likely to respond to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein, comprising: a) determining the expression level of at least 1 , 2, 3, 4, 5, 6, or 7 genes, in particular at least the genes, selected from the group consisting of: Kinesin family member 23, Topoisomerase (DNA) Il binding protein 1 , Structural maintenance of chromosomes 4, Aurora kinase B, SMA4, RALBP1 associated Eps domain containing 2 and Dmx-like 2, in cells of the individual suffering from CML; b) comparing the determined expression level for each gene respectively to a predetermined reference expression level; c) deducing therefrom if the individual suffering from CML is at risk of developing resistance to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein or if the individual is likely to respond to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein.

Preferably, in the above-defined first determination method, the determination of the expression level is further carried out for at least one of the genes, preferably at least the genes, selected from the group consisting of: DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 11 (CHL1 -like helicase homolog, S. cerevisiae), Centromere protein P, Schlafen family member 13, RAD51 -like 1 (S. cerevisiae), BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast), Origin recognition complex subunit 6 like (yeast), unassigned EST preferably represented by SEQ ID NO: 14, Enhancer of zeste homolog 2 (Drosophila), Nucleopohn 85kDa, Glucuronidase, beta pseudogene 1 , Fanconi anemia, complementation group A gene, Polymerase (DNA directed) theta , unassigned EST preferably represented by SEQ ID NO: 20, Phosphodiesterase 4D cAMP- specific (phosphodiesterase E3 dunce homolog, Drosophila), 2-deoxyribose-5- phosphate aldolase homolog (C elegans).

More preferably, in the above-defined first determination method the determination of the expression level is further carried out for at least one of the genes, in particular at least the genes, selected from the group consisting of: KIAA1212, Ubiquitin specific peptidase 31 , Plasminogen-like B1 , Zinc finger protein 738, Essential meiotic endonuclease 1 homolog 1 (S. pombe), Zinc finger homeobox 1 b, RAD54-like (S. cerevisiae), mutS homolog 5 (E. coli), RAB1 1 family interacting protein 3 (class II), M-phase phosphoprotein 9, Polycystic kidney disease 2 (autosomal dominant), Similar to Beta-glucuronidase precursor, Forkhead box P1 , unassigned EST preferably represented by SEQ ID NO: 36, Est variant gene 6 (TEL oncogene), unassigned EST preferably represented by SEQ ID NO:38, Serologically defined colon cancer antigen 8, Purinergic receptor P2X ligand-gated ion channel 1 , Thyroid hormone receptor associated protein 2, Remodeling and spacing factor 1 , unassigned EST preferably represented by SEQ ID NO: 43, unassigned EST preferably represented by SEQ ID NO: 44, Similar to phosphodiesterase 4D cAMP specific, unassigned EST preferably represented by SEQ ID NO: 46, THO complex 2, Myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila) translocated to 10, unassigned EST preferably represented by SEQ ID NO: 49, AT rich interactive domain 1 B (SWH -like), DnaJ (Hsp40) homolog (subfamily C member 1 ), Ubiquitin-conjugating enzyme E2E 1 (UBC4/5 homolog, yeast), U2-associated SR140 protein, Dachshund homolog 1 (Drosophila), KIAA0220-like protein, Cyclin E1 , Ring finger protein 13, SYS1 Golgi-localized integral membrane protein homolog (S. cerevisiae), Ring finger protein 38, LMBR1 domain containing 1 , Phosphatase and tensin homolog (mutated in multiple advanced cancers 1 ), Oxysterol binding protein-like 8, unassigned EST preferably represented by SEQ ID NO: 70, C-type lectin domain family 4 member A, SH3-domain GRB2-like endophilin B1 , KIAA1949, Low density lipoprotein receptor-related protein 10, unassigned EST preferably represented by SEQ ID NO: 68, KIAA2018, unassigned EST preferably represented by SEQ ID NO: 70, unassigned EST preferably represented by SEQ ID NO: 71 , Phosphatidylinositol binding clathrin assembly protein, Coiled-coil domain containing 91 , C-type lectin domain family 4 member E, Immunoglobulin (CD79A) binding protein 1 , Serine/threonine kinase 17b (apoptosis-inducing), Ubiquitin specific peptidase 7 (herpes virus-associated), RAS p21 protein activator 2, Leukocyte receptor cluster (LRC) member 1 , Receptor accessory protein 5, KIAA1128, Heme oxygenase (decycling) 2, Zinc finger protein 652, Zinc fingers and homeoboxes 2, Oxysterol binding protein-like 1 1 , unassigned EST preferably represented by SEQ ID NO: 86, Family with sequence similarity 49 member B, Stromal membrane-associated protein 1 -like, unassigned EST preferably represented by SEQ ID NO: 89, CD53 molecule, Nuclear receptor coactivator 1 , LSM10 U7 small nuclear RNA associated, Transmembrane emp24 protein transport domain containing 5, Ribosomal protein S6 kinase 9OkDa polypeptide 3, CD300a molecule. The present invention also relates to an alternative first method, preferably an in vitro method, for determining if an individual suffering from chronic myeloid leukemia (CML) is at risk of developing resistance to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein or if the individual is likely to respond to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein, comprising: a) determining the expression level of at least 1 , 2, or 3 of the genes, in particular at least all the genes, selected from the group consisting of: RAD51 -like 1 (S. cerevisiae), Aurora kinase B, and Phosphatase and tensin homolog (mutated in multiple advanced cancers 1 ); b) comparing the determined expression level for each gene respectively to a predetermined reference expression level; c) deducing therefrom if the individual suffering from CML is at risk of developing resistance to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein or if the individual is likely to respond to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein.

Preferably, in the above-defined alternative first determination method, the determination of the expression level is further carried out for at least 1 , 2, 3, 4, 5, 6, 7, 8 or 9 of the genes, preferably at least all the genes, selected from the group consisting of:

Kinesin family member 23, DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 11 (CHL1 -like helicase homolog, S. cerevisiae), Centromere protein P, BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast), Structural maintenance of chromosomes 4, Enhancer of zeste homolog 2 (Drosophila), Fanconi anemia, complementation group A gene, Essential meiotic endonuclease 1 homolog 1 (S. pombe), and RAD54-like (S. cerevisiae).

More preferably, in the above-defined alternative first determination method, the determination of the expression level is further carried out for at least one of the genes, preferably at least all the genes, selected from the group consisting of:

Origin recognition complex subunit 6 like (yeast), Polymerase (DNA directed) theta, Topoisomerase (DNA) Il binding protein 1 , SMA4, RALBP1 associated Eps domain containing 2, Dmx-like 2, Schlafen family member 13, unassigned EST preferably represented by SEQ ID NO: 14, Nucleopohn 85kDa, Glucuronidase, beta pseudogene 1 , unassigned EST preferably represented by SEQ ID NO: 20, Phosphodiesterase 4D cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila), 2-deoxyhbose-5-phosphate aldolase homolog (C. elegans), KIAA1212, Ubiquitin specific peptidase 31 , Plasminogen-like B1 , Zinc finger protein 738, Zinc finger homeobox 1 b, mutS homolog 5 (E. coli), RAB1 1 family interacting protein 3 (class II), M-phase phosphoprotein 9, Polycystic kidney disease 2 (autosomal dominant), Similar to Beta-glucuronidase precursor, Forkhead box P1 , unassigned EST preferably represented by SEQ ID NO: 36, Ets variant gene 6 (TEL oncogene), unassigned EST preferably represented by SEQ ID NO: 38, Serologically defined colon cancer antigen 8, Purinergic receptor P2X ligand-gated ion channel 1 , Thyroid hormone receptor associated protein 2, Remodeling and spacing factor 1 , unassigned EST preferably represented by SEQ ID NO: 43, unassigned EST preferably represented by SEQ ID NO: 44, Similar to phosphodiesterase 4D cAMP specific, unassigned EST preferably represented by SEQ ID NO: 46, THO complex 2, Myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila) translocated to 10, unassigned EST preferably represented by SEQ ID NO: 49, AT rich interactive domain 1 B (SWH -like), DnaJ (Hsp40) homolog (subfamily C member 1 ), Ubiquitin-conjugating enzyme E2E 1 (UBC4/5 homolog, yeast), U2-associated SR140 protein, Dachshund homolog 1 (Drosophila), KIAA0220-like protein, Cyclin E1 , Ring finger protein 13, SYS1 Golgi-localized integral membrane protein homolog (S. cerevisiae), Ring finger protein 38, LMBR1 domain containing 1 , Oxysterol binding protein-like 8, unassigned EST preferably represented by SEQ ID NO: 63, C-type lectin domain family 4 member A, SH3-domain GRB2-like endophilin B1 , KIAA1949, Low density lipoprotein receptor-related protein 10, unassigned EST preferably represented by SEQ ID NO: 68, KIAA2018, unassigned EST preferably represented by SEQ ID NO: 70, unassigned EST preferably represented by SEQ ID NO: 71 , Phosphatidylinositol binding clathrin assembly protein, Coiled-coil domain containing 91 , C-type lectin domain family 4 member E, Immunoglobulin (CD79A) binding protein 1 , Serine/threonine kinase 17b (apoptosis-inducing), Ubiquitin specific peptidase 7 (herpes virus-associated), RAS p21 protein activator 2, Leukocyte receptor cluster (LRC) member 1 , Receptor accessory protein 5, KIAA1128, Heme oxygenase (decycling) 2, Zinc finger protein 652, zinc fingers and homeoboxes 2, Oxysterol binding protein-like 1 1 , unassigned EST preferably represented by SEQ ID NO: 86, Family with sequence similarity 49 member B, Stromal membrane-associated protein 1 -like, unassigned EST preferably represented by SEQ ID NO: 89, CD53 molecule, Nuclear receptor coactivator 1 , LSM10 U7 small nuclear RNA associated, Transmembrane emp24 protein transport domain containing 5, Ribosomal protein S6 kinase 9OkDa polypeptide 3, CD300a molecule. The invention also relates to a second method, preferably an in vitro method, for determining if an individual suffering from chronic myeloid leukemia (CML) is at risk of developing resistance to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein or if the individual is likely to respond to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein, comprising: a) determining the expression level of at least one gene, or of genes, involved in DNA repair by homologous recombination in cells of the individual suffering from CML; b) comparing the determined expression level for each gene respectively to a predetermined reference expression level; c) deducing therefrom if the individual suffering from CML is at risk of developing resistance to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein or if the individual is likely to respond to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein.

Preferably, in the above-defined second determination method, the determination of the expression level is further carried out for at least 1 , 2, 3, 4, 5, 6, 7, or 8 of the genes, in particular the genes, involved in DNA repair by homologous recombination selected from the group consisting of: RAD51 -like 1 (S. cerevisiae), RAD54-like (S. cerevisiae), Essential meiotic endonuclease 1 homolog 1 (S. pombe), Enhancer of zeste homolog 2 (Drosophila), Origin recognition complex subunit 6 like (yeast), Polymerase (DNA directed) theta, Structural maintenance of chromosomes 4, DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 11 (CHL1 -like helicase homolog, S. cerevisiae), Topoisomerase (DNA) Il binding protein 1.

More preferably, in the above-defined second determination method, the determination of the expression level is further carried out for at least one of the genes, preferably at least the genes, selected from the group consisting of: Kinesin family member 23, Aurora kinase B, SMA4, RALBP1 associated Eps domain containing 2, Dmx-like 2, Centromere protein P, Schlafen family member 13, BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast), unassigned EST preferably represented by SEQ ID NO: 14, Nucleoporin 85kDa, Glucuronidase, beta pseudogene 1 , Fanconi anemia, complementation group A gene, unassigned EST preferably represented by SEQ ID NO: 20, Phosphodiesterase 4D cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila), 2-deoxyhbose-5-phosphate aldolase homolog (C. elegans), KIAA1212, Ubiquitin specific peptidase 31 , Plasminogen-like B1 , Zinc finger protein 738, Zinc finger homeobox 1 b, mutS homolog 5 (E. coli), RAB1 1 family interacting protein 3 (class II), M-phase phosphoprotein 9, Polycystic kidney disease 2 (autosomal dominant), Similar to Beta-glucuronidase precursor, Forkhead box P1 , unassigned EST preferably represented by SEQ ID NO: 36, Ets variant gene 6 (TEL oncogene), unassigned EST preferably represented by SEQ ID NO: 38, Serologically defined colon cancer antigen 8, Purinergic receptor P2X ligand-gated ion channel 1 , Thyroid hormone receptor associated protein 2, Remodeling and spacing factor 1 , unassigned EST preferably represented by SEQ ID NO: 43, unassigned EST preferably represented by SEQ ID NO: 44, Similar to phosphodiesterase 4D cAMP specific, unassigned EST preferably represented by SEQ ID NO: 46, THO complex 2, Myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila) translocated to 10, unassigned EST preferably represented by SEQ ID NO: 49, AT rich interactive domain 1 B (SWH -like), DnaJ (Hsp40) homolog (subfamily C member 1 ), Ubiquitin-conjugating enzyme E2E 1 (UBC4/5 homolog, yeast), U2-associated SR140 protein, Dachshund homolog 1 (Drosophila), KIAA0220-like protein, Cyclin E1 , Ring finger protein 13, SYS1 Golgi-localized integral membrane protein homolog (S. cerevisiae), Ring finger protein 38, LMBR1 domain containing 1 , Phosphatase and tensin homolog (mutated in multiple advanced cancers 1 ), Oxysterol binding protein-like 8, unassigned EST preferably represented by SEQ ID NO: 63, C-type lectin domain family 4 member A, SH3-domain GRB2-like endophilin B1 , KIAA1949, Low density lipoprotein receptor-related protein 10, unassigned EST preferably represented by SEQ ID NO: 68, KIAA2018, unassigned EST preferably represented by SEQ ID NO: 70, unassigned EST preferably represented by SEQ ID NO: 71 , Phosphatidylinositol binding clathrin assembly protein, Coiled-coil domain containing 91 , C-type lectin domain family 4 member E, Immunoglobulin (CD79A) binding protein 1 , Serine/threonine kinase 17b (apoptosis-inducing), Ubiquitin specific peptidase 7 (herpes virus-associated), RAS p21 protein activator 2, Leukocyte receptor cluster (LRC) member 1 , Receptor accessory protein 5, KIAA1128, Heme oxygenase (decycling) 2, Zinc finger protein 652, zinc fingers and homeoboxes 2, Oxysterol binding protein-like 1 1 , unassigned EST preferably represented by SEQ ID NO: 86, Family with sequence similarity 49 member B, Stromal membrane-associated protein 1 -like, unassigned EST preferably represented by SEQ ID NO: 89, CD53 molecule, Nuclear receptor coactivator 1 , LSM10 U7 small nuclear RNA associated, Transmembrane emp24 protein transport domain containing 5, Ribosomal protein S6 kinase 9OkDa polypeptide 3, CD300a molecule.

In a preferred embodiment of the above-defined first and second determination methods, it is deduced that the individual is at risk of developing resistance to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein:

- if the following genes are overexpressed with respect to their respective predetermined reference expression level: Kinesin family member 23, Topoisomerase (DNA) Il binding protein 1 , Structural maintenance of chromosomes 4, Aurora kinase B, SMA4, , DEAD/H (Asp-Glu-Ala- Asp/His) box polypeptide 1 1 (CHL1 -like helicase homolog, S. cerevisiae), Centromere protein P, Schlafen family member 13, RAD51 -like 1 (S. cerevisiae), BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast), Origin recognition complex subunit 6 like (yeast), unassigned EST preferably represented by SEQ ID NO: 14, Enhancer of zeste homolog 2 (Drosophila), Nucleopohn 85kDa, Glucuronidase beta pseudogene 1 , Fanconi anemia complementation group A gene, Polymerase (DNA directed) theta, unassigned EST preferably represented by SEQ ID NO: 20, Phosphodiesterase 4D cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila), 2-deoxyribose-5-phosphate aldolase homolog (C. elegans), KIAA1212, Ubiquitin specific peptidase 31 , Plasminogen-like B1 , Zinc finger protein 738, Essential meiotic endonuclease 1 homolog 1 (S. pombe), Zinc finger homeobox 1 b, RAD54-like (S. cerevisiae), mutS homolog 5 (E. coli), RAB1 1 family interacting protein 3 (class II), M-phase phosphoprotein 9, Polycystic kidney disease 2 (autosomal dominant), Similar to Beta-glucuronidase precursor, Forkhead box P1 , unassigned EST preferably represented by SEQ ID NO: 36, Ets variant gene 6 (TEL oncogene), Unclassified EST corresponding to sequence BF930294, Serologically defined colon cancer antigen 8, Purinergic receptor P2X ligand-gated ion channel 1 , Thyroid hormone receptor associated protein 2, Remodeling and spacing factor 1 , unassigned EST preferably represented by SEQ ID NO: 43, unassigned EST preferably represented by SEQ ID NO: 44, Similar to phosphodiesterase 4D cAMP specific, unassigned EST preferably represented by SEQ ID NO: 46, THO complex 2, Myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila) translocated to 10, unassigned EST preferably represented by SEQ ID NO: 49, AT rich interactive domain 1 B (SWH -like), DnaJ (Hsp40) homolog (subfamily C member 1 ), Ubiquitin-conjugating enzyme E2E 1 (UBC4/5 homolog, yeast), U2- associated SR140 protein, Dachshund homolog 1 (Drosophila), KIAA0220-like protein, Cyclin E1 ; and

- if the following genes are underexpressed with respect to their respective predetermined reference expression level: RALBP1 associated Eps domain containing 2 Dmx-like 2, Ring finger protein 13, SYS1 Golgi-localized integral membrane protein homolog (S. cerevisiae), Ring finger protein 38, LMBR1 domain containing 1 , Phosphatase and tensin homolog (mutated in multiple advanced cancers 1 ), Oxysterol binding protein-like 8, unassigned EST preferably represented by SEQ ID NO: 63, C-type lectin domain family 4 member A, SH3-domain GRB2-like endophilin B1 , KIAA1949, Low density lipoprotein receptor-related protein 10, unassigned EST preferably represented by SEQ ID NO: 68, KIAA2018, unassigned EST preferably represented by SEQ ID NO: 70, unassigned EST preferably represented by SEQ ID NO: 71 , Phosphatidylinositol binding clathrin assembly protein, Coiled-coil domain containing 91 , C-type lectin domain family 4 member E, Immunoglobulin (CD79A) binding protein 1 , Serine/threonine kinase 17b (apoptosis-inducing), Ubiquitin specific peptidase 7 (herpes virus-associated), RAS p21 protein activator 2, Leukocyte receptor cluster (LRC) member 1 , Receptor accessory protein 5, KIAA1128, Heme oxygenase (decycling) 2, Zinc finger protein 652, zinc fingers and homeoboxes 2, Oxysterol binding protein-like 1 1 , unassigned EST preferably represented by SEQ ID NO: 86, Family with sequence similarity 49 member B, Stromal membrane-associated protein 1 -like, unassigned EST preferably represented by SEQ ID NO: 89, CD53 molecule, Nuclear receptor coactivator 1 , LSM10 U7 small nuclear RNA associated, Transmembrane emp24 protein transport domain containing 5, Ribosomal protein S6 kinase 9OkDa polypeptide 3, CD300a molecule.

The present invention also relates to a third method, preferably an in vitro method, for determining if an individual suffering from chronic myeloid leukemia (CML) is at risk of developing resistance to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein or if the individual is likely to respond to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein, comprising: a) determining the quantity of mRNAs from cells of the individual suffering from CML, or duplicates and/or replicates thereof, liable to hybridize under stringent conditions to the probes comprising or consisting of SEQ ID NO: 96 to 103, fragments of SEQ ID NO: 96 to 103 of at least 10 nucleotides, or sequences complementary to SEQ ID NO: 96 to 103 or to the fragments thereof; b) comparing the determined quantity for each mRNA or duplicate and/or replicate thereof respectively to a predetermined reference quantity of the mRNA or duplicate and/or replicate thereof; c) deducing therefrom if the individual suffering from CML is at risk of developing resistance to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein or if the individual is likely to respond to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein.

Preferably, in the above-defined third determination method, the determination of the quantity is further carried out at least for the probes comprising or consisting of SEQ ID NO: 104 to 124, fragments of SEQ ID NO: 104 to 124 of at least 10 nucleotides, or sequences complementary to SEQ ID NO: 104 to 124 or to the fragments thereof.

More preferably, in the above-defined third determination method, the determination of the quantity is further carried out at least for the probes comprising or consisting of SEQ ID NO: 125 to 198, fragments of SEQ ID NO: 125 to 198 of at least 10 nucleotides, or sequences complementary to SEQ ID NO: 125 to 198 or to the fragments thereof.

The present invention also relates to a method for treating an individual suffering from CML comprising: - determining from the above-defined first, second, or third determination method if an individual suffering from chronic myeloid leukemia (CML) is at risk of developing resistance to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein or if the individual is likely to respond to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein,

- administering the individual suffering from CML with a therapeutically effective amount of a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein, if the individual has been determined as likely to respond to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein; or - administering the individual suffering from CML with a therapeutically effective amount of a compound intended to treat CML other than a compound targeting the BCR-ABL fusion protein, if the individual has been determined as being at risk of developing resistance to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein.

Detailed description of the invention

Chronic myeloid leukemia (CML) is well known in the art and is notably described in MeIo et al. (2007) Nat Rev Cancer 7:441 -453.

As intended herein, the expression "tyrosine kinase inhibitor targeting the BCR-ABL fusion protein" relates to any compound liable to inhibit the tyrosine kinase activity of the BCR-ABL fusion protein. The BCR-ABL fusion protein is notably described in Lugo et al. (1990) Science 247:1079-1082. In particular, the tyrosine kinase inhibitor targeting the BCR-ABL fusion protein is a competitive inhibitor of ATP binding to the protein. Preferably, within the frame of the present invention the tyrosine kinase inhibitor targeting the BCR-ABL fusion protein is imatinib. lmatinib is well known in the art and is notably sold under the trademark Glivec®. It is notably described in Buchdunger et al. (2000) J Pharmacol Exp Ther 295:139-145. As intended herein, imatinib relates to imatinib alone or to imatinib mesylate. As intended herein, the expression "resistance to treatment" indicates that after one year of treatment with imatinib at the recommended dosage, the individual presents more than 95% of Ph-positive metaphases, preferably 100% Ph-positive metaphases, i.e. no degree of cytogenetic response. Such individuals are also called non-responders.

As intended herein the expression "responding to treatment" indicates that after one year of treatment with imatinib at the recommended dosage, the individual presents less than 1 % of Ph-positive metaphases, preferably no Ph- positive metaphases, i.e. the individuals present complete cytogenetic response (CCyR). Such individuals are also called responders.

Determining the number of Ph-positive metaphases is generally carried out on cells from bone marrow aspirates and preferably on at least 20 metaphases. A Ph-positive metaphase is a metaphase wherein a Philadelphia chromosome can be identified. Determining the number of Ph-positive metaphases can be carried by methods well-known to one of skill in the art and notably described in Kaeda et al. (2002) Acta Haematol 107:64-75.

As intended herein the expression "at risk of developing resistance" or "likely to respond to treatment" relates to the prediction of the individual response to the treatment with a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein. In particular, the determination method of the invention is carried out in individuals who have not been treated with a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein or have been treated with such an inhibitor for less than a year. As intended herein, the expression "predetermined reference expression level" is a level of expression of genes corresponding to that which can be seen in cells of responder individual. Similarly, the expression "predetermined reference quantity" corresponds to the quantity of mRNAs which can be seen in cells of responder individual or duplicates and/or replicates thereof. Thus, preferably, the predetermined reference expression level is the expression level of the genes in cells of individuals suffering from CML treated by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein and presenting no resistance thereto. Similarly, preferably, the predetermined reference quantity is the quantity of mRNAs in cells of individuals suffering from CML treated by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein and presenting no resistance thereto, or the quantity of duplicates and/or replicates of said mRNAs.

As intended herein, the expression "cells of the individual" relates in particular to cells or to biological samples containing cells of the myeloid lineage, such as peripheral blood mononuclear cells (PMBCs) or cells from a bone marrow aspirate, and more particularly to CD34+ cells.

As intended herein, a "compound intended to treat CML other than a compound targeting the BCR-ABL fusion protein" relates to any compound which does not act by inhibiting the tyrosine kinase activity of the BCR-ABL fusion protein. Preferably, such a compound is selected from the group consisting of an

Aurora kinase inhibitor, such as MK 0457 (VX -680, Merck), AZD1 152 (Astra

Zeneca) or Danusertib Hydrochloride (PHA-739358), an inhibitor of the PI3/Akt pathway, such as BAG956 (Novartis Pharma, Basel, Switzerland), LY294002 or TNF-α, or an inhibitor of the mTOR pathway, such as Temsirolimus (CCI-779,

Wyeth Pharmaceuticals).

The PI3/Akt pathway is well known to one of skill in the art and is notably defined in Berns et al. (2007) Cancer Cell 12:395-402.

As intended herein, "determining the expression level" of a gene can be carried out by any suitable method known in the art. In particular, it can be assessed by quantifying the mRNAs and/or the proteins encoded by the genes.

Thus, expression can be determined at the protein level, by measuring the levels of polypeptides encoded by the gene products described herein, or biological activity thereof. Such methods are well known in the art and include, for example immunoassays based on antibodies to proteins encoded by the genes.

Numerous methods are known in the art for quantifying mRNAs, such as quantitative reverse-transcription-based polymerase chain reaction (RT-PCR) assays using primers specific for the mRNA sequences, or methods wherein mRNAs, or duplicates and/or replicates thereof, are hybridized under stringent conditions with probes.

Within the frame of the invention it is preferred that the expression level of the genes is determined by quantifying the mRNAs encoded by these genes, or duplicates and/or replicates thereof.

Besides, it is preferred that the quantification of RNAs, or duplicates and/or replicates thereof, is obtained trough hybridization under stringent conditions with probes according to the invention. Most preferably, the probes according to the invention are arrayed on microarrays. Methods for quantifying RNAs, or duplicates and/or replicates thereof, hybridized to probes are well known to one of skill in the art and notably involve, where duplicates and/or replicates of mRNAs are used, labelling the duplicates and/or replicates with detectable labels, such as biotine for instance. The labelling of the duplicates and/or replicates can proceed through incorporation of labelled nucleotides either within polynucleotide chain constituting the duplicates and/or replicates or at its extremities.

As intended herein the expression "liable to hybridize under stringent conditions" indicates that the mRNAs or the duplicates thereof can specifically bind pairwise, essentially by forming Watson-Chck-type pairs (e.g. G-C pairs or U-A pairs), with probes having sequences complementary thereto. Adequate stringent conditions according to the invention can be easily determined by one of skill in the art. Preferred stringent conditions according to the invention comprise a hybridization step of 10 to 20 hours, preferably 16 hours, at about 40 to 55 °C, preferably 50 °C, under an ionic strength equivalent to that provided by 500 mM to 2 M NaCI, preferably 1 M NaCI. Additional compounds well known to one skilled in the art can also be added such as pH buffers (e.g. Tris or MES), EDTA, Tween, Bovine Serum Albumin, and herring sperm DNA.

As intended herein a "duplicate and/or replicate" of mRNA molecule of single or double-stranded RNA or DNA molecule comprising or consisting of the sequence of the mRNA or of the complementary sequence of said mRNA (e.g. cDNA or cRNA). Duplicates and/or replicates can be easily obtained by one of skill in the art by adequately combining the use of a reverse-transchptase (Ae. a RNA- dependent DNA polymerase), a DNA-dependent DNA polymerase, a DNA- dependent RNA polymerase or a RNA-dependent RNA polymerase, according to methods well known in the art. Preferably, the probes according to the invention comprise or consist of

SEQ ID NO: 104 to 206, fragments of SEQ ID NO: 104 to 206 of at least 10 nucleotides, or sequences complementary to SEQ ID NO: 104 to 206 or to the fragments thereof.

As intended herein, the fragments of SEQ ID NO: 104 to 206 comprise at least 10 nucleotides, more preferably at least 20 nucleotides. Preferably also, the fragments of SEQ ID NO: 96 to 198 comprise at the most 50 nucleotides, more preferably 30 nucleotides. Most preferably, the fragments of SEQ ID NO: 96 to 198 comprise from 20 to 30 nucleotides, in particular 25 nucleotides. It is particularly preferred within the frame of the present invention that the probes according to the invention are constituted of sequences SEQ ID NO: 199- 1353.

SEQ ID NO: 199-1353 are fragments of about 25 nucleotides derived from the sequences SEQ ID NO: 96-198. The following table summarizes (i) the genes which expression level the probes of SEQ ID NO: 199-1353 are liable to determine, (ii) the sequence (SEQ ID NO: 104-206) from which the probes are derived, and (iii) the names of the Affymetrix® probe sets constituted of the indicated subsets of probes:

In general, the genes mentioned herein are identified by names well known to one of skilled in the art. A complete description of these genes can notably be obtained from the Entrez Gene database (www.ncbi.nlm.nih.gov).

A complete description, of the genes according to the invention is also provided by the following table:

As intended herein, the expression "preferably represented by SEQ ID NO:" indicates that the mRNA encoded by the genes according to the invention preferably comprises or consists of a sequence represented by the respective SEQ ID NOs listed in the above table, or of homologous sequences presenting at least 80%, more preferably at least 90%, and most preferably 95% identity with said respective SEQ ID NOs, provided that said homologous sequences encode proteins having the same function as that of the corresponding genes listed in the table.

As intended herein, "EST" represent an Expressed Sequence Tag. An unassigned EST corresponds to a mRNA which function is being established.

EXAMPLE

Methods

1. Patient characteristics and response assessment

Thirteen CML patients in chronic pahse (CP) were treated with 400 mg imatinib mesylate (Glivec®) daily (Table 1). The minimal follow up was 24 month.

The patients were classified according to their cytogenetic responses as "responders" and "non-responders". Cytogenetics was performed on bone marrow (BM) aspirates according to standard protocols (Kaeda et al (op. cit.)). BCR-ABL transcripts were measured in the blood at 6-to-12 week intervals using real-time quantitative PCR (RQ-PCR) (Kaeda et al {op. cit.)).

Table 1 : Patient characteristics

The responder group comprised 8 patients who achieved complete cytogenetic response (CCyR) within the first year of treatment and were still in CCyR at latest follow up. The non-responder group, who were regarded as examples of primary resistance, comprised 5 patients who failed to achieve any degree of cytogenetic response (Ae. >95% Ph-positive) during follow up. The study was approved by the inventors institutional review board. All patients signed an informed consent. 2. Selection of high-quality leukemic RNA extract

For each patient, peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centhfugation (Lymphoprep; Nycomed, Oslo, Norway) before starting imatinib. Total RNA was extracted using the Qiagen RNeasy kit (Qiagen, Hilden, Germany). RNA quality was assayed by Bioanalyser 2100 (Agilent, Palo Alto, CA, USA). Informed consent for the use of those samples was obtained in accordance with the Declaration of Helsinki and with the approval from the Institutional Review Board.

3. Gene expression profiling using DNA microarravs

Gene expression profiling of 15 samples was performed using Affymethx® (Santa Clara, CA, USA) U133 Plus 2.0 human oligonucleotide microarrays from 2 μg total RNA. Scanning was done using Affymethx® GeneArray scanner and quantification with Affymetrix® Command console software.

4. Oligonucleotide microarrav hybridization

Experiments were performed according to the standard protocols available from the manufacturer. Synthesis of first-strand cDNA was done using 2μg of total RNA by T7-oligo(dT) priming followed by second-strand cDNA synthesis. After purification, in vitro transcription associated with amplification generated cRNA containing biotinylated pseudouhdine. Biotinylated cRNA was purified, quantified and chemically fragmented (95 °C for 35 minutes), then hybridized to microarrays in 200ml hybridization buffer at 45 °C for 16 hours. Automated washes and staining with streptavidin-phycoerythhn were done as recommended. Double signal amplification was done by biotinylated antistreptavidin antibody with goat-lgG blocking antibody.

5. Microarrav analysis and statistical procedures Data were analyzed by the Robust Multichip Average method in R using

Bioconductor and associated packages. Robust Multichip Average (RMA) did background adjustment, quantile normalization, and summarization of 1 1 oligonucleotides per gene. Before analysis, a filtering process removed from the data set the genes with low and poorly measured expression as defined by an expression value inferior to 100 units in all 15 CP-CML samples, retaining 24,863 genes/expressed sequence tags (ESTs) with expression values ranging from 5 to 30,700 (mean, 156). To identify and rank genes discriminating samples from responder and non-responder patients, supervised analysis was applied to the 24,863 genes/ESTs. A signal-to- noise ratio (SNR) was calculated for each gene as SNR = (M1 - M2) / (S1 + S2), where M1 and S1 , respectively, represent mean and SD of expression levels of the gene in group 1 , and M2 and S2 in group 2. Confidence levels were estimated by 100 random permutations of samples as previously described. The chosen significance threshold for SNR ensured that the number of genes selected by chance never exceeded the number of identified discriminator genes. The lists of discriminator genes were interrogated by Ingenuity Pathway Analysis (version 5.5.1 -1002; Ingenuity Systems, Redwood City, CA). Once identified, the classification power of the gene profiling was illustrated by classifying samples according to the correlation coefficient of their expression profile with the median profile of the "non-responders" samples. A "leave-one-out" (LOO) procedure was applied as cross-validation (CV) of the generated greedy equivalent search (GES).

6. Validation on independent datasets

The results of the gene expression study were tested on two independent gene expression datasets collected from the EBI public repository (http://www.ebi.ac.uk/arrayexpress/) in which pretreatment CP-CML samples had been profiled using Affymetrix® U133A microarrays. In the first dataset (Frank et al. (2006) Leukemia 20:1400-1407) (accession number E-MEXP-433), gene profiles from 30 responding patients (defined as MCyR at 12 months) and 15 non- responding patients (defined as lack of MCyR at 12 months) were analyzed. In the second dataset (Yong et al. (2006) Blood 107:205-212), 10 patients with an 'aggressive disease' (blastic transformation (BT) within 3 years of diagnosis) had been compared with 9 patients with an indolent disease' (BT after 7 or more years from diagnosis), all of whom had been treated with interferon but not with imatinib. Results

105 probe sets were identified, representing 95 unique sequences (9 ESTs and 86 genes) as differentially expressed between the 8 responder and 5 non- responder samples (the theoretical number of false positives is <5). Compared with the responders the non-responders had 64 probe sets overexpressed (5

ESTs and 50 genes) and 41 underexpressed (4 ESTs and 36 genes) (Table 2).

Of the 50 overexpressed genes in the non-responders Ingenuity Pathway Analysis identified 16 genes involved in the 'Cell Cycle', (p=3,56E-07), 16 involved in ONA Replication, Recombination and Repair' (p=0, 00026) and 13 involved in 'Cellular Growth and Proliferation' (p=0.00486). Of the 36 underexpressed genes in the non-responders one was the tumor suppressor gene PTEN.

The resulting classification of 13 samples correlated perfectly with the cytogenetic response to imatinib. By leave-one-out cross-validation, 92% of samples were correctly assigned (p=0.0047, Fisher's exact test). Gene expression profiling was performed on cells from two additional CP patients (not referred to above) who could best be classified as having 'acquired resistance'. Both had achieved CCyR within 1 year but then lost their responses at 18 and 24 months respectively. These two patients had the same expression profiles as the non-responders. An attempt was made at assessing the expression of the 105 differentially expressed probe sets which had been identified in an independent set of 45 CP- CIVIL cases that had either achieved MCyR (n=30) or not (n=15) after 12 months imatinib (Frank et al. {op. cit.)). Although the definition of resistance to imatinib used in this validation set was slightly different from the inventors definition, the classification of samples based on the expression of 80 common probe sets tallied closely with the inventors results results, with a sensitivity and a specificity of 73% (p=0.004, Fisher's exact test).

This is the first study in which the gene expression pattern observed in imatinib resistant CML-CP patients has been validated in an independent set. The results were also compared with those of a second set of 19 CML CP patients treated with interferon-α. Ten patients had an aggressive disease (see above) and 9 patients an indolent disease (Yong et al. (op.cit.)). In this study examination of the expression of the 80 common probe sets suggested the gene expression pattern which was identified could identify patients with an aggressive disease independently of any imatinib therapy (70% sensitivity, 78% specificity). This suggests that patients classified as having a relatively more aggressive disease might well be patients who would have responded poorly to imatinib (Frank et al. (op. cit.)).

In this study cells from non-responders overexpressed genes encoding several proteins, notably RAD51 L1 , RAD54L, EME1 , EZH2, ORC6L, POLQ, SMC4, DDX1 1 and TOPBP1 involved in DNA replication and repair by homologous recombination (HR). Complex DNA damage is repaired by HR and also by non-homologous end-joining, both of which have been reported to be defective in CML (MeIo et al. (2007) Nat Rev Cancer 7:441 -453, Nowicki et al. (2004) Blood 104:3746-3753). One might speculate that non-responding patients have accumulated relatively high levels of genotoxic agents, such as reactive oxygen species (Koptyra et al. (2006) Blood 108:319-327, Rassool et al. (2007) 67:8762-8771 ), in their BCR-ABL positive cells and that high expression of genes involved in repair mechanisms is a secondary though possibly relatively ineffective response (Nowicki et al (op. cit), Koptyra et al. (op. cit), Rassool et al. (op. cit), Slupianek et al. (2006) DNA repair 5:243-250, Cross et al. (2008) Leukemia in press). The observation that the tumor suppressor gene PTEN was underexpressed in non-responders is of interest. This might permit activation of the BCR-ABL- independent PI3K/AKT pathway and thereby enhance resistance to imatinib and proliferation of the leukemic clone, as already described in some tumors (Berns et al. (2007) Cancer Cell 12:395-402, Jhawer et al. (2008) Cancer Res 68:1953- 1961 ). Because nuclear PTEN regulates RAD51 its low expression might also contribute to increased genomic instability (Shen et al. (2007) Cell 128(1 ):157-70). In summary the pattern of gene expression which is described in patients resistant to imatinib might help identify patients destined to fare badly when treated with this agent. RefSeq

Gene

Probe Set ID* P- Gene Name Transcript Status value Symbol ID

<1 E- Overexpressed

244427_at 07 KIF23 Kinesin family member 23 AW 192521 in resistant

DEAD/H (Asp-Glu-Ala-

Asp/His) box polypeptide 1 1

5,01 E- (CHL1 -like helicase Overexpressed

208149_x_at 07 DDX11 homolog, S. cerevisiae) NM_030653 in resistant

1 ,00E- Overexpressed

1556347_at 06 CENPP Centromere protein P W72151 in resistant

1 ,50E- Overexpressed

1558217_at 06 SLFN13 schlafen family member 13 AK074465 in resistant

1 ,50E- Overexpressed

1570166_a_at 06 RAD51 L1 RAD51 -like 1 (S. cerevisiae) BC020846 in resistant

BUB1 budding uninhibited

3,01 E- by benzimidazoles 1 Overexpressed

233445_at 06 BUB1 homolog (yeast) AK022040 in resistant

3,01 E- origin recognition complex, Overexpressed

219105_x_at 06 ORC6L subunit 6 like (yeast) NM_014321 in resistant

DEAD/H (Asp-Glu-Ala-

Asp/His) box polypeptide 1 1

3,51 E- (CHL1 -like helicase Overexpressed

208159 x at 06 DDX11 homolog, S. cerevisiae) NM_004399 in resistant

1556589_at or 3,51 E- CDNA FLJ25645 fis, clone Overexpressed

1556590_s_at 06 ... SYN00113 T83966 in resistant

4,51 E- Structural maintenance of Overexpressed

237246_at 06 SMC4 chromosomes 4 AI797163 in resistant

8,02E- Enhancer of zeste homolog Overexpressed

215006_at 06 EZH2 2 (Drosophila) AK023816 in resistant

8,52E- Overexpressed

218014_at 06 NUP85 nucleoporin 85kDa NM_024844 in resistant

1 ,00E- Overexpressed

239219_at 05 AURKB aurora kinase B N55457 in resistant

1 ,40E- glucuronidase, beta Overexpressed

232889_at 05 GUSBP1 pseudogene 1 AU147591 in resistant

1 ,50E- Fanconi anemia, Overexpressed

236976_at 05 FANCA complementation group A AI569792 in resistant

1 ,55E- polymerase (DNA directed), Overexpressed

207746_at 05 POLQ theta NM_014125 in resistant

1 ,55E- chromosome 21 open Overexpressed

220918_at 05 C21orf96 reading frame 96 NM_025143 in resistant

Phosphodiesterase 4D, cAMP-specific

1 ,55E- (phosphodiesterase E3 Overexpressed

1556331_a_at 05 PDE4D dunce homolog, Drosophila) BC035063 in resistant

2-deoxyribose-5-phosphate

1 ,95E- aldolase homolog (C. Overexpressed

230892_at 05 DERA elegans) AI912194 in resistant

2,00E- Overexpressed

1562648_at 05 KIAA1212 KIAA1212 BC035848 in resistant

2,56E- Ubiquitin specific peptidase Overexpressed

239348 at 05 USP31 31 AI285970 in resistant

1558837_a_at 2,56E- Overexpressed or 05 PLGLB1 Plasminoαen-like B1 BQ024490 in resistant 1558836_at

2,71 E- Overexpressed

229700_at 05 ZNF738 zinc finger protein 738 BE966267 in resistant essential meiotic

3,01 E- endonuclease 1 homolog 1 Overexpressed

234464_s_at 05 EME1 (S. pombe) AK021607 in resistant

3,01 E- Overexpressed

235593_at 05 ZFHX1 B zinc finger homeobox 1 b AL546529 in resistant

3,01 E- Overexpressed

242737_at 05 RAD51 L1 RAD51 -like 1 (S. cerevisiae) AW293315 in resistant

3,36E- Overexpressed

204558_at 05 RAD54L RAD54-like (S. cerevisiae) NM_003579 in resistant

3,41 E- Overexpressed

212913_at 05 MSH5 mutS homolog 5 (E. coli) BE674960 in resistant

3,41 E- RAB11 family interacting Overexpressed

228613_at 05 RAB11 FIP3 protein 3 (class II) BF183535 in resistant

3,46E- Overexpressed

1558369_at 05 MPHOSPH9 M-phase phosphoprotein 9 BC036600 in resistant

3,76E- Polycystic kidney disease 2 Overexpressed

240370_at 05 PKD2 (autosomal dominant) AI432451 in resistant

3,81 E- Similar to Beta- Overexpressed

213605_s_at 05 LOC728411 glucuronidase precursor AL049987 in resistant

3,81 E- Overexpressed

240666_at 05 FOXP1 Forkhead box P1 AI732568 in resistant

4,21 E- Overexpressed

244387_at 05 ... Transcribed locus AW979271 in resistant

4,26E- Ets variant gene 6 (TEL Overexpressed

240498_at 05 ETV6 oncogene) AA704891 in resistant

4,26E- CDNA FLJ34664 fis, clone Overexpressed

1559117_at 05 ... LIVER2000592 BF930294 in resistant

4,46E- Serologically defined colon Overexpressed

243963_at 05 SDCCAG8 cancer antigen 8 AI473707 in resistant

4,91 E- glucuronidase, beta Overexpressed

213089_at 05 GUSBP1 pseudogene 1 AU 158490 in resistant

5,11 E- purinergic receptor P2X, Overexpressed

210401_at 05 P2RX1 ligand-gated ion channel, 1 U45448 in resistant

DEAD/H (Asp-Glu-Ala-

Asp/His) box polypeptide 1 1

5,56E- (CHL1 -like helicase Overexpressed

213378_s_at 05 DDX11 homolog, S. cerevisiae) AI983033 in resistant

5,86E- Thyroid hormone receptor Overexpressed

239561_at 05 THRAP2 associated protein 2 AA780679 in resistant

6,06E- Overexpressed

215761_at 05 DMXL2 Dmx-like 2 AK000156 in resistant

6,26E- Remodeling and spacing Overexpressed

215786_at 05 RSF1 factor 1 AK022170 in resistant

6,46E- Overexpressed

240652_at 05 ... ... T91029 in resistant

6,51 E- chromosome 20 open Overexpressed

226670_S_at 05 C20orf119 reading frame 119 AL109839 in resistant

Similar to

6,51 E- phosphodiesterase 4D, Overexpressed

222322_at 05 LOC653198 cAMP specific AI791860 in resistant

7,12E- Chromosome 10 open Overexpressed

216211_at 05 C10orf18 reading frame 18 AL049233 in resistant

7,22E- Overexpressed

230651_at 05 THOC2 THO complex 2 AI018256 in resistant 7,47E- structural maintenance of Overexpressed

215623_x_at 05 SMC4 chromosomes 4 AK002200 in resistant

Myeloid/lymphoid or mixed- lineage leukemia (trithorax

7,87E- homolog, Drosophila); Overexpressed

243003_at 05 MLLT10 translocated to, 10 AV702197 in resistant

7,87E- enhancer of zeste homolog Overexpressed

203358_s_at 05 EZH2 2 (Drosophila) NM_004456 in resistant

8,27E- CDNA FLJ11504 fis, clone Overexpressed

232586_x_at 05 — HEMBA1002119 AU 144503 in resistant

8,52E- AT rich interactive domain Overexpressed

1558822_at 05 ARID1 B 1 B (SWH -like) AF147412 in resistant

8,67E- DnaJ (Hsp40) homolog, Overexpressed

242216_at 05 DNAJC1 subfamily C, member 1 AI791832 in resistant

8,92E- Overexpressed

215599_at 05 SMA4 SMA4 X83300 in resistant

Ubiquitin-conjugating

8,92E- enzyme E2E 1 (UBC4/5 Overexpressed

236062_at 05 UBE2E1 homolog, yeast) Al 742722 in resistant

8,97E- U2-associated SR140 Overexpressed

236696_at 05 SR140 protein BE464843 in resistant

9,17E- Fanconi anemia, Overexpressed

203805_s_at 05 FANCA complementation group A AW 083279 in resistant

9,17E- Dachshund homolog 1 Overexpressed

1567101 _at 05 DACH1 (Drosophila) AF147347 in resistant

9,52E- Overexpressed

215123_at 05 LOC23117 KIAA0220-like protein AL049250 in resistant

9,57E- Topoisomerase (DNA) Il Overexpressed

1561924_at 05 TOPBP1 binding protein 1 AF085997 in resistant

9,62E- Overexpressed

213523_at 05 CCNE1 cyclin E1 AI671049 in resistant

9,77E- Underexpressed

201780_s_at 05 RNF13 ring finger protein 13 NM_007282 in resistant

SYS1 Golgi-localized

9,32E- integral membrane protein Underexpressed

224668_at 05 SYS1 homolog (S. cerevisiae) N30607 in resistant

8,27E- Underexpressed

218528_s_at 05 RNF38 ring finger protein 38 NM_022781 in resistant

7,87E- Underexpressed

218191_s_at 05 LMBRD1 LMBR1 domain containing 1 NM_018368 in resistant phosphatase and tensin homolog (mutated in

7,62E- multiple advanced cancers Underexpressed

204054_at 05 PTEN 1 ) NM_000314 in resistant

7,57E- oxysterol binding protein-like Underexpressed

212585_at 05 OSBPL8 8 BF970829 in resistant

7,02E- Underexpressed

230570_at 05 — Transcribed locus AI702465 in resistant

6,46E- C-type lectin domain family Underexpressed

219947_at 05 CLEC4A 4, member A NM_016184 in resistant

6,41 E- SH3-domain GRB2-like Underexpressed

209090_s_at 05 SH3GLB1 endophilin B1 AL049597 in resistant

5,61 E- Underexpressed

224927_at 05 KIAA1949 KIAA1949 BG251556 in resistant

5,51 E- low density lipoprotein Underexpressed

201412_at 05 LRP10 receptor-related protein 10 NM_014045 in resistant

228991_at 5,51 E- ... CDNA FLJ27143 fis, clone BF707423 Underexpressed 05 SPL09242 in resistant

5,31 E- Underexpressed

227433_ .at 05 KIAA2018 KIAA2018 AI651814 in resistant

5,16E- CDNA FLJ34311 fis, clone Underexpressed

229319_ .at 05 — FEBRA2008255 AA057585 in resistant

4,51 E- chromosome 10 open Underexpressed

224665_ .at 05 C10orf104 reading frame 104 BE874771 in resistant

4,31 E- phosphatidylinositol binding Underexpressed

212511_ .at 05 PICALM clathrin assembly protein AI766247 in resistant

3,91 E- coiled-coil domain Underexpressed

218545_ .at 05 CCDC91 containing 91 NM_018318 in resistant

3,91 E- C-type lectin domain family Underexpressed

219859_, .at 05 CLEC4E 4, member E NM_014358 in resistant

3,66E- immunoglobulin (CD79A) Underexpressed

202105_ .at 05 IGBP1 binding protein 1 NM_001551 in resistant

3,36E- Serine/threonine kinase 17b Underexpressed

226525_ .at 05 STK17B (apoptosis-inducing) N51102 in resistant

3,36E- ubiquitin specific peptidase Underexpressed

201499_ _s_at 05 USP7 7 (herpes virus-associated) NM_003470 in resistant

3,31 E- RALBP1 associated Eps Underexpressed

227425_ .at 05 REPS2 domain containing 2 AI984607 in resistant

3,26E- Underexpressed

226392_ .at 05 RASA2 RAS p21 protein activator 2 AI888503 in resistant

2,81 E- leukocyte receptor cluster Underexpressed

232018_ .at 05 LENG1 (LRC) member 1 AI701895 in resistant

2,41 E- Underexpressed

208873_ _s_at 05 REEP5 receptor accessory protein 5 BC000232 in resistant

2,31 E- Underexpressed

209379_ _s_at 05 KIAA1 128 KIAA1128 AF241785 in resistant

2,15E- heme oxygenase Underexpressed

218120_ _s_at 05 HMOX2 (decycling) 2 D21243 in resistant

1 ,90E- Underexpressed

225266_ .at 05 ZNF652 Zinc finger protein 652 AA526904 in resistant

1 ,70E- zinc fingers and Underexpressed

203556_, .at 05 ZHX2 homeoboxes 2 NM_014943 in resistant

1 ,70E- oxysterol binding protein-like Underexpressed

222586_ _s_at 05 OSBPL1 1 11 AI884890 in resistant

1 ,60E- chromosome 10 open Underexpressed

224664_ .at 05 C10orf104 reading frame 104 BE962336 in resistant

1 ,05E- chromosome 1 open Underexpressed

218165_, .at 05 C1orf149 reading frame 149 NM_022756 in resistant

8,52E- family with sequence Underexpressed

217916_ _s_at 06 FAM49B similarity 49, member B NM_016623 in resistant

8,52E- stromal membrane- Underexpressed

225282_ .at 06 SMAP1 L associated protein 1 -like AL137764 in resistant

8,52E- Underexpressed

212764_ .at 06 — — AI806174 in resistant

5,51 E- Underexpressed

203416 at 06 CD53 CD53 molecule NM_000560 in resistant

209105_, .at 5,51 E- nuclear receptor coactivator Underexpressed

06 NCOA1 1 AI672428 in resistant

4,51 E- LSM10, U7 small nuclear Underexpressed

225593_ _at 06 LSM10 RNA associated AL542359 in resistant transmembrane emp24

4,01 E- protein transport domain Underexpressed

242263_ _at 06 TMED5 containing 5 BE620297 in resistant 1 ,50E- ribosomal protein S6 kinase, Underexpressed

226335_at 06 RPS6KA3 9OkDa, polypeptide 3 BG498334 in resistant

<1 E- Underexpressed

209933_s_at 07 CD300A CD300a molecule AF020314 in resistant

Table 2: List of probe sets differentially expressed between the responders and the non- responders CML patients.

All the cited bibliographical references are incorporated herein by reference.

Claims

Claims

1. A method for determining if an individual suffering from chronic myeloid leukemia (CML) is at risk of developing resistance to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein or if the individual is likely to respond to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein, comprising: a) determining the expression level of at least one of the genes selected from the group consisting of: RAD51 -like 1 (S. cerevisiae), Aurora kinase B, and Phosphatase and tensin homolog (mutated in multiple advanced cancers 1 ); b) comparing the determined expression level for each gene respectively to a predetermined reference expression level; c) deducing therefrom if the individual suffering from CML is at risk of developing resistance to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein or if the individual is likely to respond to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein.

2. The method of claim 1 , wherein the determination of the expression level is further carried out for at least one of the genes selected from the group consisting of: Kinesin family member 23, DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 1 1 (CHLI -like helicase homolog, S. cerevisiae), Centromere protein P, BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast), Structural maintenance of chromosomes 4, Enhancer of zeste homolog 2 (Drosophila), Fanconi anemia, complementation group A gene, Essential meiotic endonuclease 1 homolog 1 (S. pombe), and RAD54-like (S. cerevisiae).

3. The method of claim 1 or 2, wherein the determination of the expression level is further carried out for at least one of the genes selected from the group consisting of: Origin recognition complex subunit 6 like (yeast), Polymerase (DNA directed) theta, Topoisomerase (DNA) Il binding protein 1 , SMA4, RALBP1 associated Eps domain containing 2, Dmx-like 2, Schlafen family member 13, unassigned EST preferably represented by SEQ ID NO: 14, Nucleopohn 85kDa, Glucuronidase, beta pseudogene 1 , unassigned EST preferably represented by SEQ ID NO: 20, Phosphodiesterase 4D cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila), 2-deoxyribose-5-phosphate aldolase homolog (C elegans), KIAA1212, Ubiquitin specific peptidase 31 , Plasminogen-like B1 , Zinc finger protein 738, Zinc finger homeobox 1 b, mutS homolog 5 (E. coli), RAB1 1 family interacting protein 3 (class II), M-phase phosphoprotein 9, Polycystic kidney disease 2 (autosomal dominant), Similar to Beta-glucuronidase precursor, Forkhead box P1 , unassigned EST preferably represented by SEQ ID NO: 36, Ets variant gene 6 (TEL oncogene), unassigned EST preferably represented by SEQ ID NO: 38, Serologically defined colon cancer antigen 8, Purinergic receptor P2X ligand-gated ion channel 1 , Thyroid hormone receptor associated protein 2, Remodeling and spacing factor 1 , unassigned EST preferably represented by SEQ ID NO: 43, unassigned EST preferably represented by SEQ ID NO: 44, Similar to phosphodiesterase 4D cAMP specific, unassigned EST preferably represented by SEQ ID NO: 46, THO complex 2, Myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila) translocated to 10, unassigned EST preferably represented by SEQ ID NO: 49, AT rich interactive domain 1 B (SWH -like), DnaJ (Hsp40) homolog (subfamily C member 1 ), Ubiquitin-conjugating enzyme E2E 1 (UBC4/5 homolog, yeast), U2-associated SR140 protein, Dachshund homolog 1 (Drosophila), KIAA0220-like protein, Cyclin E1 , Ring finger protein 13, SYS1 Golgi-localized integral membrane protein homolog (S. cerevisiae), Ring finger protein 38, LMBR1 domain containing 1 , Oxysterol binding protein-like 8, unassigned EST preferably represented by SEQ ID NO: 63, C-type lectin domain family 4 member A, SH3-domain GRB2-like endophilin B1 , KIAA1949, Low density lipoprotein receptor-related protein 10, unassigned EST preferably represented by SEQ ID NO: 68, KIAA2018, unassigned EST preferably represented by SEQ ID NO: 70, unassigned EST preferably represented by SEQ ID NO: 71 , Phosphatidylinositol binding clathrin assembly protein, Coiled-coil domain containing 91 , C-type lectin domain family 4 member E, Immunoglobulin (CD79A) binding protein 1 , Serine/threonine kinase 17b (apoptosis-inducing), Ubiquitin specific peptidase 7 (herpes virus-associated), RAS p21 protein activator 2, Leukocyte receptor cluster (LRC) member 1 , Receptor accessory protein 5, KIAA1128, Heme oxygenase (decycling) 2, Zinc finger protein 652, zinc fingers and homeoboxes 2, Oxysterol binding protein-like 1 1 , unassigned EST preferably represented by SEQ ID NO: 86, Family with sequence similarity 49 member B, Stromal membrane-associated protein 1 -like, unassigned EST preferably represented by SEQ ID NO: 89, CD53 molecule, Nuclear receptor coactivator 1 , LSM10 U7 small nuclear RNA associated, Transmembrane emp24 protein transport domain containing 5, Ribosomal protein S6 kinase 9OkDa polypeptide 3, CD300a molecule.

4. A method for determining if an individual suffering from chronic myeloid leukemia (CML) is at risk of developing resistance to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein or if the individual is likely to respond to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein, comprising: a) determining the expression level of at least one gene involved in DNA repair by homologous recombination in cells of the individual suffering from CML; b) comparing the determined expression level for each gene respectively to a predetermined reference expression level; c) deducing therefrom if the individual suffering from CML is at risk of developing resistance to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein or if the individual is likely to respond to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein.

5. The method of claim 4, wherein the genes involved in DNA repair by homologous recombination are selected from the group consisting of: RAD51 -like 1 (S. cerevisiae), RAD54-like (S. cerevisiae), Essential meiotic endonuclease 1 homolog 1 (S. pombe), Enhancer of zeste homolog 2 (Drosophila), Origin recognition complex subunit 6 like (yeast), Polymerase (DNA directed) theta, Structural maintenance of chromosomes 4, DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 11 (CHL1 -like helicase homolog, S. cerevisiae), Topoisomerase (DNA) Il binding protein 1.

6. The method of claim 4 or 5, wherein the determination of the expression level is further carried out for at least one of the genes selected from the group consisting of: Kinesin family member 23, Aurora kinase B, SMA4, RALBP1 associated Eps domain containing 2, Dmx-like 2, Centromere protein P, Schlafen family member 13, BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast), unassigned EST preferably represented by SEQ ID NO: 14, Nucleopohn 85kDa, Glucuronidase, beta pseudogene 1 , Fanconi anemia, complementation group A gene, unassigned EST preferably represented by SEQ ID NO: 20, Phosphodiesterase 4D cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila), 2-deoxyhbose-5-phosphate aldolase homolog (C elegans), KIAA1212, Ubiquitin specific peptidase 31 , Plasminogen-like B1 , Zinc finger protein 738, Zinc finger homeobox 1 b, mutS homolog 5 (E. coli), RAB1 1 family interacting protein 3 (class II), M-phase phosphoprotein 9, Polycystic kidney disease 2 (autosomal dominant), Similar to Beta-glucuronidase precursor, Forkhead box P1 , unassigned EST preferably represented by SEQ ID NO: 36, Ets variant gene 6 (TEL oncogene), unassigned EST preferably represented by SEQ ID NO: 38, Serologically defined colon cancer antigen 8, Purinergic receptor P2X ligand-gated ion channel 1 , Thyroid hormone receptor associated protein 2, Remodeling and spacing factor 1 , unassigned EST preferably represented by SEQ ID NO: 43, unassigned EST preferably represented by SEQ ID NO: 44, Similar to phosphodiesterase 4D cAMP specific, unassigned EST preferably represented by SEQ ID NO: 46, THO complex 2, Myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila) translocated to 10, unassigned EST preferably represented by SEQ ID NO: 49, AT rich interactive domain 1 B (SWH -like), DnaJ (Hsp40) homolog (subfamily C member 1 ), Ubiquitin-conjugating enzyme E2E 1 (UBC4/5 homolog, yeast), U2-associated SR140 protein, Dachshund homolog 1 (Drosophila), KIAA0220-like protein, Cyclin E1 , Ring finger protein 13, SYS1 Golgi-localized integral membrane protein homolog (S. cerevisiae), Ring finger protein 38, LMBR1 domain containing 1 , Phosphatase and tensin homolog (mutated in multiple advanced cancers 1 ), Oxysterol binding protein-like 8, unassigned EST preferably represented by SEQ ID NO: 63, C-type lectin domain family 4 member A, SH3-domain GRB2-like endophilin B1 , KIAA1949, Low density lipoprotein receptor-related protein 10, unassigned EST preferably represented by SEQ ID NO: 68, KIAA2018, unassigned EST preferably represented by SEQ ID NO: 70, unassigned EST preferably represented by SEQ ID NO: 71 , Phosphatidylinositol binding clathrin assembly protein, Coiled-coil domain containing 91 , C-type lectin domain family 4 member E, Immunoglobulin (CD79A) binding protein 1 , Serine/threonine kinase 17b (apoptosis-inducing), Ubiquitin specific peptidase 7 (herpes virus-associated), RAS p21 protein activator 2, Leukocyte receptor cluster (LRC) member 1 , Receptor accessory protein 5, KIAA1128, Heme oxygenase (decycling) 2, Zinc finger protein 652, zinc fingers and homeoboxes 2, Oxysterol binding protein-like 1 1 , unassigned EST preferably represented by SEQ ID NO: 86, Family with sequence similarity 49 member B, Stromal membrane-associated protein 1 -like, unassigned EST preferably represented by SEQ ID NO: 89, CD53 molecule, Nuclear receptor coactivator 1 , LSM10 U7 small nuclear RNA associated, Transmembrane emp24 protein transport domain containing 5, Ribosomal protein S6 kinase 9OkDa polypeptide 3, CD300a molecule.

7. The method of any of claims 1 to 6, wherein it is deduced that the individual is at risk of developing resistance to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein:

- if the following genes are overexpressed with respect to their respective predetermined reference expression level: Kinesin family member 23, Topoisomerase (DNA) Il binding protein 1 , Structural maintenance of chromosomes 4, Aurora kinase B, SMA4, , DEAD/H (Asp-Glu-Ala- Asp/His) box polypeptide 1 1 (CHL1 -like helicase homolog, S. cerevisiae), Centromere protein P, Schlafen family member 13, RAD51 -like 1 (S. cerevisiae), BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast), Origin recognition complex subunit 6 like (yeast), unassigned EST preferably represented by SEQ ID NO: 14, Enhancer of zeste homolog 2 (Drosophila), Nucleoporin 85kDa, Glucuronidase beta pseudogene 1 , Fanconi anemia complementation group A gene, Polymerase (DNA directed) theta, unassigned EST preferably represented by SEQ ID NO: 20, Phosphodiesterase 4D cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila), 2-deoxyribose-5-phosphate aldolase homolog (C. elegans), KIAA1212, Ubiquitin specific peptidase 31 , Plasminogen-like B1 , Zinc finger protein 738, Essential meiotic endonuclease 1 homolog 1 (S. pombe), Zinc finger homeobox 1 b, RAD54-like (S. cerevisiae), mutS homolog 5 (E. coli), RAB1 1 family interacting protein 3 (class II), M-phase phosphoprotein 9, Polycystic kidney disease 2 (autosomal dominant), Similar to Beta-glucuronidase precursor, Forkhead box P1 , unassigned EST preferably represented by SEQ ID NO: 36, Ets variant gene 6 (TEL oncogene), Unclassified EST corresponding to sequence BF930294, Serologically defined colon cancer antigen 8, Purinergic receptor P2X ligand-gated ion channel 1 , Thyroid hormone receptor associated protein 2, Remodeling and spacing factor 1 , unassigned EST preferably represented by SEQ ID NO: 43, unassigned EST preferably represented by SEQ ID NO: 44, Similar to phosphodiesterase 4D cAMP specific, unassigned EST preferably represented by SEQ ID NO: 46, THO complex 2, Myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila) translocated to 10, unassigned EST preferably represented by SEQ ID NO: 49, AT rich interactive domain 1 B (SWH -like), DnaJ (Hsp40) homolog (subfamily C member 1 ), Ubiquitin-conjugating enzyme E2E 1 (UBC4/5 homolog, yeast), U2- associated SR140 protein, Dachshund homolog 1 (Drosophila), KIAA0220-like protein, Cyclin E1 ;

- and if the following genes are underexpressed with respect to their respective predetermined reference expression level:

RALBP1 associated Eps domain containing 2 Dmx-like 2, Ring finger protein 13, SYS1 Golgi-localized integral membrane protein homolog (S. cerevisiae), Ring finger protein 38, LMBR1 domain containing 1 , Phosphatase and tensin homolog (mutated in multiple advanced cancers 1 ), Oxysterol binding protein-like 8, unassigned EST preferably represented by SEQ ID NO: 63, C-type lectin domain family 4 member A, SH3-domain GRB2-like endophilin B1 , KIAA1949, Low density lipoprotein receptor-related protein 10, unassigned EST preferably represented by SEQ ID NO: 68, KIAA2018, unassigned EST preferably represented by SEQ ID NO: 70, unassigned EST preferably represented by SEQ ID NO: 71 , Phosphatidylinositol binding clathrin assembly protein, Coiled-coil domain containing 91 , C-type lectin domain family 4 member E, Immunoglobulin (CD79A) binding protein 1 , Serine/threonine kinase 17b (apoptosis-inducing), Ubiquitin specific peptidase 7 (herpes virus-associated), RAS p21 protein activator 2, Leukocyte receptor cluster (LRC) member 1 , Receptor accessory protein 5, KIAA1128, Heme oxygenase (decycling) 2, Zinc finger protein 652, zinc fingers and homeoboxes 2, Oxysterol binding protein-like 1 1 , unassigned EST preferably represented by SEQ ID NO: 86, Family with sequence similarity 49 member B, Stromal membrane-associated protein 1 -like, unassigned EST preferably represented by SEQ ID NO: 89, CD53 molecule, Nuclear receptor coactivator 1 , LSM10 U7 small nuclear RNA associated, Transmembrane emp24 protein transport domain containing 5, Ribosomal protein S6 kinase 9OkDa polypeptide 3, CD300a molecule.

8. The method of any of claims 1 to 7, wherein the predetermined reference expression level is the expression level of the genes in cells of individuals suffering from CML treated by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein and presenting no resistance thereto.

9. The method of any of claims 1 to 8, wherein the expression level of the genes is measured by quantifying the respective mRNAs of said genes, or duplicates and/or replicates thereof

10. The method of any of claims 1 to 8, wherein the expression level of the genes is obtained trough hybridization under stringent conditions with probes comprising or consisting of sequences selected from the group consisting of SEQ ID NO: 104 to 206, fragments of SEQ ID NO: 104 to 206 of at least 10 nucleotides, or sequences complementary to SEQ ID NO: 104 to 206 or to the fragments thereof.

11. The method of claim 10, wherein the probes are arrayed on a microarray.

12. The method of any of claims 1 to 11 , wherein the tyrosine kinase inhibitor targeting the BCR-ABL fusion protein is imatinib.

13. The method of any of claims 1 to 12, wherein the cells are peripheral blood mononuclear cells (PMBCs).

14. A method for treating an individual suffering from CML comprising:

- determining from the method of any of claims 1 to 13 if an individual suffering from chronic myeloid leukemia (CML) is at risk of developing resistance to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein or if the individual is likely to respond to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein,

- administering the individual suffering from CML with a therapeutically effective amount of a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein, if the individual has been determined as likely to respond to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein; or

- administering the individual suffering from CML with a therapeutically effective amount of a compound intended to treat CML other than a compound targeting the BCR-ABL fusion protein, if the individual has been determined as being at risk of developing resistance to treatment by a tyrosine kinase inhibitor targeting the BCR-ABL fusion protein.

15. The method of claim 14, wherein the tyrosine kinase inhibitor targeting the BCR-ABL fusion protein is imatinib.

16. The method of claim 14 or 15, wherein the compound intended to treat CML other than a compound targeting the BCR-ABL fusion protein is selected from the group consisting of an Aurora kinase inhibitor and an inhibitor of the PI3/Akt pathway.