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

Cody Paiva, Taylor A. Rowland, Bhargava Sreekantham, Claire Godbersen, Scott R. Best, Prabhjot Kaur, Marc Loriaux, Stephen Spurgeon, Olga V. Danilova, Alexey Danilov

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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 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 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.

Original languageEnglish (US)
Pages (from-to)1890-1900
Number of pages11
JournalHaematologica
Volume102
Issue number11
DOIs
StatePublished - Oct 27 2017

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B-Cell Chronic Lymphocytic Leukemia
B-Lymphocytes
TNF Receptor-Associated Factor 3
Phosphotransferases
TNF Receptor-Associated Factor 2
B-Cell Activating Factor
Apoptosis
Apoptosis Regulatory Proteins
Coculture Techniques
Cell Survival
Therapeutics
Down-Regulation
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Hematology

Cite this

SYK inhibition thwarts the BAFF - B-cell receptor crosstalk and thereby antagonizes Mcl-1 in chronic lymphocytic leukemia. / Paiva, Cody; Rowland, Taylor A.; Sreekantham, Bhargava; Godbersen, Claire; Best, Scott R.; Kaur, Prabhjot; Loriaux, Marc; Spurgeon, Stephen; Danilova, Olga V.; Danilov, Alexey.

In: Haematologica, Vol. 102, No. 11, 27.10.2017, p. 1890-1900.

Research output: Contribution to journalArticle

Paiva, Cody ; Rowland, Taylor A. ; Sreekantham, Bhargava ; Godbersen, Claire ; Best, Scott R. ; Kaur, Prabhjot ; Loriaux, Marc ; Spurgeon, Stephen ; Danilova, Olga V. ; Danilov, Alexey. / SYK inhibition thwarts the BAFF - B-cell receptor crosstalk and thereby antagonizes Mcl-1 in chronic lymphocytic leukemia. In: Haematologica. 2017 ; Vol. 102, No. 11. pp. 1890-1900.
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