The critical mechanisms underlying human hematopoietic stem cell (HSC) transformation by the BCR-ABL gene in chronic myeloid leukemia (CML) are still not well understood. Since treatment with imatinib fails to eliminate primitive CML hematopoietic cells, there is a pressing need to identify additional mechanisms that can be targeted to enhance elimination of CML stem cells. A tyrosine residue at position 177 (Y177) in the BCR-ABL protein binds the adapter protein Grb2 and appears to play an important role in BCR-ABL induced myeloid leukemogenesis in murine CML models. We have recently shown that a tyrosine to phenylalanine mutation of Y177 (Y177F) also results in significant reduction of abnormalities in proliferation and differentiation in BCR-ABL expressing human CD34+ cells and in BCR-ABL induced activation of Ras, Akt and STAT5 signaling (
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