@article{Cody Paiva_Taylor A. Rowland_Bhargava Sreekantham_Claire Godbersen_Scott R. Best_Prabhjot Kaur_Marc M. Loriaux_Stephen E.F. Spurgeon_Olga V. Danilova_Alexey V. Danilov_2017, place={Pavia, Italy}, title={SYK inhibition thwarts the BAFF - B-cell receptor crosstalk and thereby antagonizes Mcl-1 in chronic lymphocytic leukemia}, volume={102}, url={https://haematologica.org/article/view/8252}, DOI={10.3324/haematol.2017.170571}, abstractNote={Although small molecule inhibitors of B-cell receptor-associated kinases have revolutionized therapy in chronic lymphocytic leukemia (CLL), responses are incomplete. Pro-survival signaling emanating from the microenvironment may foster therapeutic resistance of the malignant B cells resident in the protective lymphoid niches. B-cell activating factor (BAFF) is critical to the 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 CLL cells, independently of <em>IGHV</em> mutational status. SYK, a proximal kinase in the B-cell receptor signaling cascade, acted <em>via</em&gt; 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 interaction with TRAF2/TRAF3 complex. Thus, SYK inhibition is a promising therapeutic strategy uniquely poised to antagonize crosstalk between BAFF and B-cell receptor, thereby disrupting the pro-survival microenvironment signaling in chronic lymphocytic leukemia.}, number={11}, journal={Haematologica}, author={Cody Paiva and Taylor A. Rowland and Bhargava Sreekantham and Claire Godbersen and Scott R. Best and Prabhjot Kaur and Marc M. Loriaux and Stephen E.F. Spurgeon and Olga V. Danilova and Alexey V. Danilov}, year={2017}, month={Oct.}, pages={1890-1900} }