[Frontiers in Bioscience 11, 198-208, January 1, 2006]
Chronic myeloid leukemia: why does it evolve from chronic phase to blast transformation?
Tariq I Mughal and John M Goldman
Division of Hematology and Oncology, University of Massachusetts Medical School, Worcester, Massachusetts and the Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA
Figure 1. The t(9;22)(q34;q11) translocation and its products: the BCR-ABL oncogene on the Ph chromosome and the reciprocal ABL-BCR on the derivative 9q+ chromosome. In the classic CML, BCR-ABL is transcribed into mRNA molecules with e13a2 or e14a2 junctions, which are then translated into the p210bcr/abl oncoprotein. This oncoprotein is a hybrid containing functional domains from the N-terminal end of BCR [dimerization domain (DD)], SRC-homology 2 (SH2)-binding and the Rho GTP-GDP sxchange factor (GEF) domains and the C-terminal end of ABL. [Only SRC-homology regions 2,3 and 1 (SH2, SH3 and SH1 respectively). Tyrosine 177 (Y177) in the BCR portion of the fusion gene and tyrosine 412 (Y412) in the ABL portion are important for the docking of adapter proteins and for BCR-ABL autophosphorylation respectively. P-S/T denotes phosphoserine and phosphothreonine.
Figure 2. Schematic representation of the possible mechanisms by which the activated p210BCR-ABL induces the clinical phenotype of CML. Though the precise mechanisms by which BCR-ABL alters stem cell kinetics remain ill-defined, it is possible that it may act by enhancing cellular proliferation; alternatively it may reduce cellular adherence. As an activated ABL opposes cellular apoptosis, the BCR-ABL gene might act by impeding 'programmed cell death' in target stem cells.
Figure 3. Signal transduction pathways involved in CML. Schematic representation of pathways that may be involved in transmitting the BCR-ABL signal to the cell nucleus in the clinical setting. Note the STAT pathway to the left, the RAS/RAF/1-MEK1 pathway centrally and the PI3 kinase/AKT pathways to the right. Molecules known to be phosphorylated by activated BCR-ABL are marked with the letter 'P'.
Figure 4. Schematic representation of the various breakpoints in the ABL and BCR genes and the encoded proteins in the BCR-ABL positive leukemias. The genes are shown at top and the RNA transcripts and corresponding proteins below. The arrow show the possible sites on breakage in the ABL gene (above) and the possible sites of the two alternative breaks in M-BCR (below) that are characteristic of CML (namely p210BCR-ABL with an e13a2 junction or 210BCR-ABL with an e14a2 junction. Breaks m-bcr and m-bcr are characteristic of Ph-positive acute lymphoblastic leukemia and Ph-positive chronic neutrophilic leukemia respectively.
Figure 5. Schematic representation of hematopoiesis: Hematopoiesis can arbitrarily be divided into a leukemia regenerating population, which is partially quiescent, but capable of generating leukemia and responsible for relapse, and a non-leukemia-regenerating population.