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Blood, 1 January 2001, Vol. 97, No. 1, pp. 277-287
NEOPLASIA
The SH2 domain of Bcr-Abl is not required to induce a murine
myeloproliferative disease; however, SH2 signaling influences disease
latency and phenotype
Xiaowu Zhang,
Ray Wong,
Sheryl X. Hao,
Warren S. Pear, and
Ruibao Ren
From the Rosenstiel Basic Medical Sciences Research
Center, Department of Biochemistry, and Department of Biology, Brandeis
University, Waltham, MA; and Department of Pathology and Institute for
Medicine and Engineering, University of Pennsylvania, Philadelphia, PA.
Bcr-Abl plays a critical role in the pathogenesis of chronic
myelogenous leukemia (CML). It was previously shown that expression of
Bcr-Abl in bone marrow cells by retroviral transduction efficiently induces a myeloproliferative disorder (MPD) in mice resembling human
CML. This in vivo experimental system allows the direct determination
of the effect of specific domains of Bcr-Abl, or specific signaling
pathways, on the complex in vivo pathogenesis of CML. In this report,
the function of the SH2 domain of Bcr-Abl in the pathogenesis of CML is
examined using this murine model. It was found that the Bcr-Abl SH2
mutants retain the ability to induce a fatal MPD but with an extended
latency compared with wild type (wt) Bcr-Abl. Interestingly, in
contrast to wt Bcr-Abl-induced disease, which is rapid and monophasic,
the disease caused by the Bcr-Abl SH2 mutants is biphasic, consisting
of an initial B-lymphocyte expansion followed by a fatal myeloid
proliferation. The B-lymphoid expansion was diminished in mixing
experiments with bcr-abl/ SH2 and wt bcr-abl
cells, suggesting that the Bcr-Abl-induced MPD suppresses B-lymphoid expansion.
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