The tyrosine kinase Syk regulates the survival of chronic lymphocytic leukemia B cells through PKCδ and proteasome-dependent regulation of Mcl-1 expression

Abstract

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by accumulation of mature monoclonal CD5 þ B cells. The disease results mainly from a failure of cells to undergo apoptosis, a process largely influenced by the existence of constitutively activated components of B-cell receptor signaling and the deregulated expression of antiapoptotic molecules. Recent evidence pointing to a critical role of spleen tyrosine kinase (Syk) in ligand-independent BCR signaling prompted us to examine its role in primary B-CLL cell survival. We demonstrate that pharmacological inhibition of constitutive Syk activity and silencing by siRNA led to a dramatic decrease of cell viability in CLL samples (n ¼ 44), regardless of clinical and biological status and induced typical apoptotic cell death with mitochondrial failure followed by caspase 3-dependent cell death. We also provide functional and biochemical evidence that Syk regulated B-CLL cell survival through a novel pathway involving PKCd and a proteasomedependent regulation of the anti-apoptotic protein Mcl-1. Together, our observations are consistent with a model wherein PKCd downstream of Syk stabilizes Mcl-1 through inhibitory phosphorylation of GSK3 by Akt. We conclude that Syk constitutes a key regulator of B-CLL cell survival, emphasizing the clinical utility of Syk inhibition in hematopoietic malignancies.

Spleen tyrosine kinase inhibition prevents chemokine- and integrin-mediated stromal protective effects in chronic lymphocytic leukemia

“…3 We and others have previously identified the B-cell receptor (BCR)-associated tyrosine kinase spleen tyrosine kinase (SYK) as a rational therapeutic target in CLL. [5][6][7][8][9][10] Pharmacologic SYK inhibition exerts prominent proapoptotic effects on CLL cells in vitro. Because SYK is primarily known as a key proximal signal transducer of the BCR, the effects of SYK inhibition in CLL are commonly interpreted as the consequence of the disruption of BCR signaling.…”

N-(4-hydroxyphenyl)retinamide promotes apoptosis of resting and proliferating B-cell chronic lymphocytic leukemia cells and potentiates fludarabine and ABT-737 cytotoxicity

“…30,31 However, PKCdelta was already active in our untreated CLLs, in accordance with previous work demonstrating constitutive activation of PKCdelta in CLL cells 40,41 and antiapoptotic, instead of death-promoting, activity in these cells. 41,42 Altogether, different from other cell systems, in CLL cells PKCdelta appeared not to participate in 4HPR apoptosis or Mcl-1 downregulation.…”

Syk Interacts with and Phosphorylates Nucleolin To Stabilize Bcl-xL mRNA and Promote Cell Survival

“…The binding of Syk to the receptor activates the enzyme, which becomes phosphorylated on tyrosine and functions as both a kinase and a scaffold to couple the receptor to downstream effectors of multiple signaling pathways. In certain malignancies of B-cell origin, it is tonic signaling from the BCR that is proposed to activate Syk to promote cell survival (4,7,8). Interestingly, the repertoire of cells in which Syk functions as a prosurvival factor extends to tumors of B-cell origin that have not yet rearranged immunoglobulin genes, hematological malignancies not of B-cell origin, and nonhematological cancers, such as retinoblastoma and certain carcinomas of the lung and pancreas (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

“…Constitutively active Syk has been reported to promote the survival of non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, and Epstein-Barr virus-associated B-cell lymphoma (3)(4)(5)(6)(7)(8)(9)(10)(11). The inhibition of Syk also promotes the differentiation of acute myeloid leukemia (AML) and attenuates the growth of AML cell lines and primary blasts (12,13).…”