Mechanistic basis of CLL resistance to targeted tumor therapy in a pathophysiologically relevant cellular context: role of Rho GTPases and phospholipase C-y2 (A08)

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Phospholipase C-y2 (PLCy2) is a hematopoietic-cell-specific signaling enzyme intimately involved in the maintenance of chronic lymphocytic leukemia (CLL) and in the acquired resistance of CLL cells to targeted CLL therapy. PLCy2 is a key player in B-cell receptor (BCR)-mediated signaling and is regulated by protein tyrosine phosphorylation as well as by certain Rho GTPases. In this project, we propose to characterize and compare the functional consequences of individual PLCy2 resistance mutations mediating targeted drug resistance in cultured neoplastic B cells with stable expression of the individual mutants, either cultured alone or in co-culture with stromal cells. The major aim is to understand the mechanistic basis of PLCy2-mediated resistance to targeted CLL therapy.