SYK inhibition thwarts the BAFF - B-cell receptor crosstalk and thereby antagonizes Mcl-1 in chronic lymphocytic leukemia.

SYK inhibition thwarts the BAFF - B-cell receptor crosstalk and thereby antagonizes Mcl-1 in chronic lymphocytic leukemia. Haematologica. 2017 Aug 24;: Authors: Paiva C, Rowland TA, Sreekantham B, Godbersen C, Best SR, Kaur P, Loriaux MM, Spurgeon SEF, Danilova OV, Danilov AV Abstract Although small molecule inhibitors of B-cell receptor-associated kinases revolutionized therapy in chronic lymphocytic leukemia, they provide for incomplete responses. Pro-survival signaling emanating from the microenvironment may foster therapeutic resistance of the malignant B-cells resident in the protective lymphoid niches. BAFF is critical in survival of both healthy and neoplastic B-cells. However, the pro-survival pathways triggered by BAFF have not been fully characterized. Here we show that BAFF elicited resistance to spontaneous and drug-induced apoptosis in stromal co-cultures, induced activation of both canonical and non-canonical NFκB signaling pathways and triggered B-cell receptor signaling in chronic lymphocytic leukemia cells, independent of IGHV mutational status. SYK, a proximal kinase in the B-cell receptor signaling cascade, acted via STAT3 to bolster transcription of the anti-apoptotic protein Mcl-1, thereby contributing to apoptosis resistance in BAFF-stimulated cells. SYK inhibitor entospletinib downregulated Mcl-1, abrogating BAFF-mediated cell survival. BAFF-B-cell receptor crosstalk in neoplastic B-cells was mediated by SYK i...
Source: Haematologica - Category: Hematology Authors: Tags: Haematologica Source Type: research