The Grb2 binding site is required for the induction of chronic myeloid leukemia-like disease in mice by the Bcr/Abl tyrosine kinase

The BCR/ABL oncogene results from a balanced translocation between chromoso mes 9 and 22 and is found in patients with chronic myeloid leukemia (CML) a nd in some patients with acute B-lymphoid leukemia. The Bcr/Abl fusion prot ein is a constitutively active tyrosine kinase that stimulates several intr acellular signaling pathways, including activation of Ras through direct bi nding of the SH2-containing adapter protein Grb2 to Bcr tyrosine 177, A tyr osine-to-phenylalanine mutation (Y177F) at this site blocks the co-associat ion of Bcr/Abl and Grb2 in vivo and impairs focus formation by Bcr/Abl in f ibroblasts. However, the Bcr/Abl Y177F mutant can transform hematopoietic c ell lines and primary bone marrow cells in vitro, so the importance of the Bcr/Abl-Grb2 interaction to myeloid and lymphoid leukemogenesis in vivo is unclear. We have recently demonstrated the efficient induction of CML-like myeloproliferative disease by BCR/ABL in a murine bone marrow transduction/ transplantation model system. The Y177F mutation greatly attenuates the mye loproliferative disease induced by BCR/ABL, with mice developing B- and T-l ymphoid leukemias of longer latency. In addition, the v-abl oncogene of Abe lson murine leukemia virus, whose protein product lacks interaction with Gr b2, is completely defective for the induction of CML-like disease. these re sults suggest that direct binding of Grb2 is required for the efficient ind uction of CML-like myeloproliferative disease by oncogenic Abl proteins. (C ) 2000 by The American Society of Hematology.