Novel Pathways for Bcr-Abl transformation

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Chromosomal rearrangements that fuse amino terminal sequences of the Bcr protein to carboxyl terminal sequences of the Abl tyrosine kinase (p210 Bcr-Abl) are associated with virtually all cases of chronic myelogenous leukemia (CML). Whereas the contribution of Abl encoded sequences to Bcr-Abl-mediated leukemogenesis are relatively well understood, the contribution from the Bcr encoded sequences is unclear. For example, several in vitro studies have identified catalytic activities within the amino terminus of Bcr, yet the relationship of these activities to the in vivo functions of Bcr, and Bcr-Abl, are not known. We have recently completed two studies which suggest that Bcr may contribute to the transforming activity of Bcr-Abl in ways that were not previously realized. First, we have identified a functional interaction between Bcr and the oncogenic transcription factor c-Myc. The disruption of this interaction may account for the elevated levels of c-Myc expression that are observed in Bcr-Abl transformed cells. Consistent with this, we have observed that c-Myc protein levels are sensitive to the dosage of Bcr in a CML-derived leukemic cell line. Second, we have demonstrated that the central RhoGEF domain of Bcr (which is retained in Bcr-Abl) contains in vivo catalytic, signaling and transforming activity. Importantly, a similar catalytic activity is observed within the context of p210 Bcr-Abl. The objective of this proposal is to characterize these new activities, and determine their fates within the context of Bcr-Abl. Specifically, we propose to (1) determine if the association of Bcr with the c-Myc transcription factor has functional consequences that contribute to Bcr-Abl-mediated transformation, and (2) determine whether the transforming and catalytic activities that we have mapped to the RhoGEF domain of Bcr contribute to Bcr-Abl-mediated transformation. The results from these studies should contribute substantially to our knowledge of the molecular basis of Philadelphia chromosome positive leukemias.