Bcr-Abl with an SH3 deletion retains the ability to induce a myeloproliferative disease in mice, yet c-Abl activated by an SH3 deletion induces only lymphoid malignancy

The bcr-abl oncogene plays a critical role in the pathogenesis of chronic m yelogenous leukemia (CML). The fusion of Bcr sequences to Abl constitutivel y activates the Abl protein tyrosine kinase. We have recently shown that ex pression of Bcr-Abr in bone marrow cells by retroviral transduction efficie ntly induces in mice a myeloproliferative disease resembling human CML and that Abl kinase activity is essential for Bcr-Abl to induce a CML-like myel oproliferative disease, Howe cer, it is not known if activation of the Abl kinase alone is sufficient to induce a myeloproliferative disease. In this study, we examined the role of the Abl SH3 domain of Bcr-Abl in induction o f myeloproliferative disease and tested whether c-Abl activated by SH3 dele tion can induce a CML-like disease. We found that Bcr-Abl with an Abl SH3 d eletion still induced a CML-like disease in mice. In contrast, c-Abl activa ted by SH3 deletion induced only lymphoid malignancies in mice and did not stimulate the growth of myeloid colonies from 5-fluorouracil-treated bone m arrow cells in vitro. These results indicate that Bcr sequences in Bcr-Abl play additional roles in inducing myeloproliferative disease beyond simply activating the Abl kinase domain and that functions of the Abl SH3 domain a re either not required or redundant in Bcr-Abl-induced myeloproliferative d isease. The results also suggest that the type of hematological neoplasm in duced by an abl oncogene is influenced not only by what type of hematopoiet ic cells the oncogene is targeted into but also by the intrinsic oncogenic properties of the particular abl oncogene. In addition, we found that Delta SH3 c-Abl induced less activation of Akt and STAT5 than did Bcr-Abl, sugge sting that activation of these pathways plays a critical role in inducing a CML-like disease.