ABL1 kinase domain mutations in Philadelphia chromosome positive acute lymphoblastic leukemia and chronic myelogenous leukemia are associated with resistance to some types of tryosine kinase inhibitor therapy. The various mutations span several hundred amino acids (M237 thru E507) and vary in their response to later generation tyrosine kinase inhibitors.

This gene is a known cancer gene.

This gene is a known cancer gene.

IKZF1(Ikaros) is a transcriptional regulator of B cell development and is believed to have tumor suppressor-like properties. Deletions (whole gene and/or partial gene deletions) of IKZF1 have been reported in approximately 15-28% of BCR-ABL1-Negative_B-cell ALL, 70-90% of BCR-ABL1-Positive B-cell ALL. IKZF1 mutations are also found in approximately 40% of "Ph-like" ALL. Loss of functions mutations (missense, nonsense, frameshift mutations) have also been reported in IKZF1 in ALL and appear to be much less common (less than 5% of cases) than deletions. Deletions and mutations in IKZF1 have been associated with adverse prognosis and greater risk of relapse.

SETBP1 encodes a protein which is believed to inhibit PP2A phosphatase activity through SET stabilization. In addition, SETBP1 binds to gDNA in AT-rich promoter regions, causing activation of a network of development genes through recruitment of a HCF1/KMT2A/PHF8 epigenetic complex. Heterozygous, somatic, missense mutations are predominantly hot-spot mutations within the SKI homologous region in exon 4, which result in the functional loss of the degron motif responsible for the short half-life of the protein. Therefore, these mutations result in an increased half-life and accumulation of the mutated SETBP1, and thus increased inhibition of the oncosupressor PP2A through the SETBP1-SET-PP2A axis. In addition, mutations in SETBP1 potentially deregulate gene transcription mediated by SETBP1. SETBP1 mutations have been described in approximately 25% of atypical chronic myelogenous leukemia, 30% of juvenile myelomonocytic leukemia, 17% of secondary acute myeloid leukemia, 13% of myeloproliferative/myelodysplastic syndrome with ring sideroblasts and thrombocytosis, and 5-15% of chronic myelomonocytic leukemia. SETPB1 mutations appear to be rare (< 5%) or absent among cases of primary acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndromes, myeloproliferative neoplasms and chronic lymphocytic leukemia. SETBP1 mutations may be seen together with mutations in other genes such as ASXL1. Mutated SETBP1 provides supportive evidence for the diagnosis of atypical chronic myeloid leukemia, BCR-ABL1-negative in the 2016 revision of the WHO classification.SETBP1 mutations are associated with disease progression in myelodysplastic syndrome (NCCN Guidelines for Myelodysplastic Syndromes), and unfavorable prognosis in chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical chronic myeloid leukemia, and MDS/MPN with ring sideroblasts associated and thrombocytosis.