Project A8 (End): Mechanistic basis of CLL resistance to targeted tumor therapy in pathophysiologically relevant cellular context: role of Rho GTPases and phospholipase C gamma2

The project is based on the observation that phospholipase C-_ϒ2 (PLC_ϒ2), a cell signaling enzyme specifically expressed in cells of hematopoietic origin, is intimately involved in maintenance of CLL and in the re-sistance of CLL cells to targeted tumor therapy by the Btk inhibitor ibrutinib. In normal and leukemic B cells, PLC_ϒ2 controls B-cell receptor (BCR)-mediated increases in [Ca²⁺] and activation of protein kinases C and is regulated by both protein tyrosine phosphorylation, e.g. by Btk, and by certain Rho GTPases such as Rac and RhoH. In this project, it is planned to extend the studies in the previous funding phase on the mecha-nisms of action of most (n=11) point mutations of PLC_ϒ2 thus far described in ibrutinib-resistant CLL pa-tients, consisting of both a moderate enhancement of basal activity and a much more marked sensitization to activated Rac. Objectives of the next funding phase are: (1) to characterize and compare the functional consequences of individual PLC_ϒ2 ibrutinib resistance mutations in the context of cultured B-cell leukemia or mantle cell lymphoma cells stably expressing these mutants; (2)  to use co-culture systems from these cells to study the effects of PLC_ϒ2 resistance mutations on the regulation of cell-cell-interaction by BCR and its co-receptors coupled to Rac activation as well as by CXC chemokine receptors known to mediate CLL cell homing to and retention in protective tissue microenvironments; and (3 to establish therapeutically-relevant epistatic relationships of and network formation by B-cell signaling components, as evidenced by the effects of other targeted CLL drugs such as the PI3K inhibitor idelalisib on malignant B cells carrying ibrutinib resistance genes; and (iv) to address the question whether the PLC_ϒ2 inhibitor RhoH plays a secondary, compensatory rather than a primary pathogenic role in B cell malignancy.

For a current list of all project-related publications, please go to this page