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Blood, 1 January 2001, Vol. 97, No. 1, pp. 4-13
PLENARY PAPER
The Src homology 2 domain of Bcr/Abl is required for efficient
induction of chronic myeloid leukemia-like disease in mice but not
for lymphoid leukemogenesis or activation of
phosphatidylinositol 3-kinase
Sergei Roumiantsev,
Isabel
E. de Aos,
Lyuba Varticovski,
Robert L. Ilaria, and
Richard A. Van
Etten
From the Center for Blood Research, Department of
Genetics, Harvard Medical School, Boston, MA; Department of Biomedical
Research, St Elizabeth's Hospital, Tufts University School of
Medicine, Boston, MA; and Hamon Center for Therapeutic Oncology
Research, University of Texas Southwestern Medical Center, Dallas, TX.
The effect of mutations in the Src homology 2 (SH2) domain of the
BCR/ABL oncogene on leukemogenesis was tested in a
quantitative murine bone marrow transduction/transplantation
assay that accurately models human Philadelphia-positive B-lymphoid
leukemia and chronic myeloid leukemia (CML). The SH2 domain was
not required for induction of B-lymphoid leukemia in mice by
BCR/ABL. Under conditions where the p190 and p210 forms of
BCR/ABL induce fatal CML-like myeloproliferative disease
within 4 weeks, p210 SH2 mutants induced CML-like disease in some mice
only after a significant delay, with other recipients succumbing to
B-lymphoid leukemia instead. In contrast, p190 BCR/ABL SH2
point and deletion mutants rapidly induced CML-like disease. These
results provide the first direct evidence of significant differences in
cell signaling by the Bcr/Abl tyrosine kinase between these distinct
leukemias. Contrary to previous observations, high levels of
phosphatidylinositol 3-kinase (PI 3-kinase) activity in primary
malignant lymphoblasts and myeloid cells from recipients of marrow
transduced with the BCR/ABL SH2 mutants were found. Hence,
the decreased induction of CML-like disease by the p210 BCR/ABL SH2 mutants is not due to impaired activation of PI
3-kinase.
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