Chronic myeloid leukemia (CML) is a progressive, often fatal, hematopoietic neoplasm characterized by the malignant expansion of pluripotent stem cells in the bone marrow. The disease comprises three clinically recognized phases - chronic, accelerated, and blastic - although not all patients follow the classic three-phase course described. 1 The initial chronic phase is typically indolent and often asymptomatic; in half of patients the disease progresses directly from the chronic to the blastic phase. 1 The biology of CML has been extensively reviewed. 2-5 CML was the first neoplastic disease for which a direct chromosomal link was found. CML represents an important model for the development of targeted therapies in cancer, because a single oncogene is responsible for initiating the disease process. 4 Cytogenetically, CML is characterized in 95 % of patients by the presence of the Philadelphia chromosome (Ph), a truncated derivative of chromosome 22 that arises following trans location of genetic material between this chromosome and chromosome 9 (t[9;22][q34;q11]). 6 The resulting fusion gene, BCR-ABL (breakpoint cluster region - Abelson murine leukemia viral proto-oncogene) codes for an abnormal, non-membrane-bound oncoprotein (p210 BCR-ABL). The oncoprotein is a constitutively active tyrosine kinase that perturbs numerous signal transduction pathways, resulting in uncontrolled cell proliferation and reduced apoptosis, or programmed cell death. 1,7 Signal transduction pathways activated by BCR-ABL may be important targets for new therapies and include Ras/Raf/mitogen activated protein kinase (MAPK), 8-13 phosphatidylinositol 3 kinase, 14-18 STAT5/Janus kinase, 19-24 and Myc. 25-28 Activation of specific signaling pathways by BCR-ABL is mediated via SRC family kinases, which may also represent a therapeutic target. 8,29 The pathogenesis of evolution from chronic phase to advanced phases of CML is not fully understood. 1 Acquisition of the BCR-ABL fusion gene increases the propensity of the Ph-positive clone to acquire additional genetic changes. Moreover, the BCR-ABL gene may acquire new mutations that allow an already genetically unstable phenotype to acquire further changes. Common gene mutations in the evolution from chronic phase to blastic phase involve the p53 gene, 30 loss of p16, INK41/arf EXON 2, 31,32 and RB. 33 Mutations can also be critical in the development of treatment resistance. Acquisition and expansion of CML clones with mutations in the ATP phosphate-binding loop (P-loop) of the kinase domain may be associated with an increased risk of disease progression and early mortality in patients treated with imatinib mesylate.34-36 This review describes the novel treatment strategies for patients who cannot obtain benefit from imatinib because of resistance or intolerance.
|Original language||English (US)|
|Title of host publication||Chronic Myeloproliferative Disorders|
|Number of pages||11|
|State||Published - Jan 1 2008|
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