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

磷脂酶C-y2 （PLCy2）是一种造血细胞特异性信号酶，密切参与慢性淋巴细胞白血病（CLL）的维持和CLL细胞对靶向CLL治疗的获得性耐药。PLCy2在b细胞受体（BCR）介导的信号传导中起关键作用，并受蛋白酪氨酸磷酸化和某些Rho gtpase的调节。在这个项目中，我们建议描述和比较单个PLCy2抗性突变在培养的肿瘤B细胞中介导靶向耐药的功能后果，这些突变在单独培养或与基质细胞共培养中稳定表达。主要目的是了解plcy2介导的CLL靶向治疗耐药的机制基础。

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.