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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 664-670
The Grb2 binding site is required for the induction of chronic
myeloid leukemia-like disease in mice by the Bcr/Abl tyrosine kinase
Ryan P. Million and
Richard A. Van Etten
From The Center for Blood Research, Department of Genetics, Harvard
Medical School, Boston, MA.
The BCR/ABL oncogene results from a balanced translocation
between chromosomes 9 and 22 and is found in patients with chronic myeloid leukemia (CML) and in some patients with acute B-lymphoid leukemia. The Bcr/Abl fusion protein is a constitutively active tyrosine kinase that stimulates several intracellular signaling pathways, including activation of Ras through direct binding of the
SH2-containing adapter protein Grb2 to Bcr tyrosine 177. A tyrosine-to-phenylalanine mutation (Y177F) at this site blocks the
co-association of Bcr/Abl and Grb2 in vivo and impairs focus formation
by Bcr/Abl in fibroblasts. However, the Bcr/Abl Y177F mutant can
transform hematopoietic cell 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 myeloproliferative disease induced by BCR/ABL, with mice developing B- and T-lymphoid leukemias of longer latency. In
addition, the v-abl oncogene of Abelson murine leukemia virus, whose protein product lacks interaction with Grb2, is completely defective for the induction of CML-like disease. These results suggest
that direct binding of Grb2 is required for the efficient induction of
CML-like myeloproliferative disease by oncogenic Abl proteins.
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