The SH2 domain of Bcr-Abl is not required to induce a murine myeloproliferative disease; however, SH2 signaling influences disease latency and phenotype

Bcr-Abl plays a critical role in the pathogenesis of chronic myelogenous le ukemia (CML), It was previously shown that expression of Bcr-Abl in bone ma rrow cells by retroviral transduction efficiently induces a myeloproliferat ive 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 pathogenes is 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 in itial B-lymphocyte expansion followed by a fatal myeloid proliferation, The B-lymphoid expansion was diminished in mixing experiments with bcr-abl/Del ta SHS and wt bcr-abl cells, suggesting that the Bcr-Abl-induced MPD suppre sses B-lymphoid expansion. (C) 2001 by The American Society of Hematology.