ifying Akt Signaling in B-Cell Chronic R phocytic Leukemia Cells

nloaded rging evidence suggests that the survival of B-cell chronic lymphocytic leukemia (CLL) cells is depenn microenvironmental influences such as antigenic stimulation and support by stromal cells. Akt, also as protein kinase B, is a central component in prosurvival signaling downstream of these events. We igated the role of Akt and its modulation by the protooncogene T-cell leukemia 1a (Tcl1a) in the al pathways of primary CLL samples and CLL-derived prolymphocytic cell lines MEC-1 and MEC-2. tivation was increased by the protective presence of human bone marrow stromal cells and B-cell or mimicking signals but antagonized by direct Akt blockade with the novel specific inhibitor AiX, with ential apoptosis induction in CLL cells with an unmutated immunoglobulin status, which predicts poor l outcome. In addition, we found a direct interaction of Akt with Tcl1a in an endogenous coimmunoitation assay. Confirming the critical role of Tcl1a in modulating Akt signaling, Akt activation was ced by overexpressing Tcl1a in CLL. In contrast, decreasing Tcl1a levels by small interfering RNA reAkt activation in the fludarabine-insensitive CLL cell line MEC-2 and sensitized the malignant cells to abine treatment. In summary, our data reveal a significant role for the Akt-Tcl1a axis in CLL survival fludar and propose a further evaluation of this interplay for targeting chemoresistance phenomena. Cancer Res; 70(18); 7336–44. ©2010 AACR.