Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of a pluripotent stem cell with a specific cytogenetic abnormality, the Philadelphia chromosome (Ph), involving myeloid, erythroid, megakaryocytic, B lymphoid, and sometimes T lymphoid cells, but not marrow fibroblasts. ... Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of a pluripotent stem cell with a specific cytogenetic abnormality, the Philadelphia chromosome (Ph), involving myeloid, erythroid, megakaryocytic, B lymphoid, and sometimes T lymphoid cells, but not marrow fibroblasts. Silver (2003) reviewed the hematologic and clinical aspects of chronic myeloid leukemia. Geary (2000) presented a historical review of CML. CML has a biphase or triphase clinical course (Medina et al., 2003). Approximately 90% of patients are diagnosed in the chronic phase, but the disease eventually evolves to a blastic phase unless successfully treated. Approximately two-thirds of patients manifest an accelerated phase. A distinct feature of disease progression is the appearance of additional cytogenetic abnormalities in the Ph-positive cells. This phenomenon, known as clonal evolution, frequently involves a second Ph, trisomy of chromosome 8, and isochromosome 17 and other abnormalities of chromosome 17 (Kantarjian et al., 1988), although other abnormalities have been described. Clonal evolution is considered a criterion of accelerated phase, although when it represents the only criterion of transformation, it is associated with a better prognosis than other criteria of accelerated phase (Cortes et al., 2003). Sawyers (1999) reviewed the clinical aspects of chronic myeloid leukemia.
Clinical studies with the Abl tyrosine kinase inhibitor STI571 in CML demonstrated that many patients with advanced-stage disease respond initially but then relapse. Through biochemical and molecular analysis of clinical material, ... - Associations with Drug Resistance Clinical studies with the Abl tyrosine kinase inhibitor STI571 in CML demonstrated that many patients with advanced-stage disease respond initially but then relapse. Through biochemical and molecular analysis of clinical material, Gorre et al. (2001) found that the drug resistance was associated with a reactivation of BCR-ABL signal transduction in all cases examined. In 6 of 9 patients, resistance was associated with a single amino acid substitution in a threonine residue of the Abl kinase domain known to form a critical hydrogen bond with the drug. This T351I substitution (189980.0001) was sufficient to confer STI571 resistance in a reconstitution experiment. In 3 patients, resistance was associated with progressive BCR-ABL gene amplification. Gorre et al. (2001) concluded that their studies provided evidence that genetically complex cancers retain dependence on an initial oncogenic event and suggest a strategy for identifying inhibitors of STI571 resistance. Azam et al. (2003) stated that sequencing of the BCR-ABL gene in patients who relapsed after STI571 chemotherapy revealed a limited set of kinase domain mutations that mediate drug resistance. To obtain a more comprehensive survey of the amino acid substitutions that confer STI571 resistance, they performed an in vitro screen of randomly mutagenized BCR-ABL and recovered all the major mutations previously identified in patients and numerous others that illuminated novel mechanisms of acquired drug resistance. Structural modeling implied that a novel class of variants acts allosterically to destabilize the autoinhibited conformation of the ABL kinase, to which STI571 preferentially binds. The authors concluded that this screening strategy is a paradigm applicable to a growing list of target-directed anticancer agents and provides a means of anticipating the drug-resistant amino acid substitutions that are likely to be clinically problematic. Goldman and Melo (2003) tabulated 19 BCR-ABL point mutations associated with resistance to the therapeutic effects of the anti-tyrosine-kinase agent, imatinib. Hantschel et al. (2007) identified the BTK tyrosine kinase (300300) and TEC kinase (600583) as major binders of the tyrosine kinase inhibitor dasatinib, which is used for treatment of BCR/ABL-positive CML. Dasatinib did not bind ITK (186973). Mutations of the gatekeeper residue in the BTK and TEC gene conferred resistance to dasatinib in cultured cells. Both BTK and TEC mutations were structurally homologous to the T315I mutation in the ABL gene that confers resistance to imatinib. Analysis of mast cells derived from Btk-deficient mice suggested that inhibition of Btk by dasatinib may be responsible for the observed reduction in histamine release upon dasatinib treatment. Dasatinib inhibited histamine release in primary human basophils and secretion of proinflammatory cytokines in immune cells. The findings suggested that dasatinib may have immunosuppressive side effects. - Genetic Modifiers Peeters et al. (1997) identified a t(9;12)(p24;p13) translocation in a patient with early pre-B acute lymphoid leukemia and a t(9;15;12)(p24;q15;p13) translocation in a patient with atypical chronic myelogenous leukemia in transformation. Both changes involved the ETV6 gene (600618) at chromosome 12p13 and the JAK2 gene (147796) at chromosome 9p24. In each case different fusion mRNAs were found, with only 1 resulting in a chimeric protein consisting of the oligomerization domain of ETV6 and the protein tyrosine kinase domain of JAK2. In bone marrow cells derived from 8 (9.41%) of 85 unrelated patients with CML during blast crisis transformation, Zhang et al. (2008) identified heterozygosity for a somatic leu359-to-val (L359V) mutation in the GATA2 gene (137295). This mutation was not present during the chronic phase of the disease. One additional patient with blast crisis and eosinophilia had an in-frame 18-bp deletion in the GATA2 gene. Both mutations were located within or close to the N terminus of the ZF2 domain, which is responsible for DNA binding, self-association, and heterodimerization. Neither mutation was detected in 200 healthy controls or in 233 patients with other forms of blood cancer. The patients with GATA2 mutations showed a poorer prognosis compared to other CML patients in blast crisis. Functional expression studies showed that the L359V mutation resulted in a gain-of-function effect with increased activity, whereas the deletion resulted in decreased activity. The L359V mutation also enhanced the inhibitory effects on the activity of PU.1 (SPI1; 165170), a major regulator of myelopoiesis. Transduction of the GATA2 L359V mutant into HL-60 cells or BCR/ABL-harboring murine cells disturbed myelomonocytic differentiation/proliferation in vitro and in vivo, respectively. These data strongly suggest that GATA2 mutations play a role in acute myeloid transformation in a subset of CML patients. - Atypical Chronic Myeloid Leukemia Atypical CML (aCML) shares clinical and laboratory features with CML but lacks the pathognomonic Philadelphia chromosome and the resulting BCR-ABL1 fusion, pointing to a different pathogenetic process. Using exome sequencing, Piazza et al. (2013) identified heteozygous somatic alterations of SETBP1 (611060) encoding a gly870 to ser (G870S) alteration in 2 of 8 aCMLs. Targeted resequencing detected SETBP1 mutations in 17 of 70 aCMLs (24.3%; 95% confidence interval = 16-35%); 16 of these mutations occurred between residues 858 and 871, within the SKI homologous region. Clinical information was available for 38 aCML cases, including 14 with SETBP1 mutations. SETBP1-mutated cases showed worse prognosis (median survival 22 vs 77 months) and presented with higher white blood cell counts at diagnosis (median of 81.0 vs 38.5 x 10(9) cells/l) compared to cases with wildtype SETBP1. No significant differences were observed in the number of peripheral blood blasts, age, hemoglobin concentration, platelet counts, or sex distribution. Piazza et al. (2013) concluded that SETBP1 mutations are present in approximately one quarter of aCML cases.