Chronic myeloid leukemia (CML) is a biphasic disease, triggered by expression of the BCR/ABL fusion gene product in hematopoietic stem cells (HSCs). HSCs can differentiate into common myeloid progenitors (CMPs), which then differentiate into progenitors for the granulocyte/macrophage cell series and lymphocyte series. The initial chronic phase of CML (CML-CP) is characterized by a massive expansion of the granulocytic-cell series. Acquisition of additional genetic mutations in addition to the expression of BCR/ABL causes the progression of CML from chronic phase to blast phase (CML-BP), characterized by an accumulation of myeloid or lymphoid blast cells.The BCR/ABL fusion gene encodes p210BCR/ABL; an oncoprotein has constitutive tyrosine kinase activity and is predominantly localized in the cytoplasm. The tyrosine kinase activity and cytoplasmic location of BCR/ABL allows the assembly of phosphorylated substrates (CBL, CRK and CRKL) in multiprotein complexes that transmit mitogenic and antiapoptotic signals via MAPK and PI3K pathways.
Additional cytogenetic and molecular alterations are frequently found in patients with CML during the progression of the disease from chronic to blast phase. These genetic changes include mutations in TP53, RB and p16INK4A, or overexpression of genes such as EVI1, resulting in cell proliferation. In addition, chromosome translocation events in CML generate the chimeric oncoprotein AML1/EVI1, which like EV1 can repress the TGFβ-mediated growth inhibitory signal.