Abstract
Chronic myelogenous leukemia (CML) is a malignant disease of hematopoietic stem cells that develops in a biphasic or triphasic course. The initial chronic phase (CML-CP) is characterized by massive expansion of granulocytic cell series. Although immature myeloid cells appear in the peripheral blood in this phase, the CML progenitor cells retain the ability to terminally differentiate. Progression of the disease after 3 to 5 years to fatal blast phase (CML-BP) is characterized by the accumulation of myeloid or lymphoid blast cells. The BCR/ABL fusion gene, a product of the t(9;22)(q34;q11) translocation found in the vast majority of human CMLs, plays an essential role in initiation as well as maintenance and progression of the disease. BCR/ABL has been found to activate many signaling pathways, including Ras, phosphatidylinositol 3-kinase, signal transducers and activators of transcription (STATs), c-Myc, and Bcl-2 or Bcl-XL, that regulate cell growth, survival, and adhesion/migration. Despite the strong mitotic activity of BCR/ABL, both clinical and laboratory studies demonstrate that BCR/ABL is not sufficient to block the terminal differentiation of myeloid cells in vivo. This indicates that the cell-autonomous developmental/differentiation program can override BCR/ABL's mitotic signal. Blocking cell differentiation seen in CML-BP is likely caused by cooperation of BCR/ABL and additional genetic abnormalities acquired during disease development.