SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma

Inhibition of constitutive and BCR-induced Syk activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic leukemia B cells

“…These DLBCL cell lines had been reported earlier to express constitutively phosphorylated and active Syk. 30 To quantify the relative phospho-Syk levels in these samples, we used as an internal standard the lymphoma B-cell line B104, which also expresses constitutively phosphorylated Syk. As shown in Figure 1c, the phospho-Syk signal in the CLL B-cell samples was equivalent to or exceeded the signal in the DLBCL cell lines, suggesting that CLL lymphocytes express substantial amounts of active Syk protein.…”

“…[27][28][29][30] Inhibition or downregulation of Syk in DLBCL and follicular lymphoma cell lines resulted in decreased phosphorylation of downstream signaling molecules and inhibition of proliferation and survival, indicating that constitutively active Syk contributes to the growth of these malignancies. 26,27,30,31 In addition, translocations involving Syk have recently been identified in patients with myelodysplastic syndrome and peripheral T-cell lymphoma, further suggesting that this kinase may function as a proto-oncogene. These translocations generate fusion proteins in which the tyrosine kinase domain of Syk is joined to the dimerization domain of the transcription factor TEL or to the N-terminal pleckstrin homology domain of the inducible T cell kinase.…”

Overexpression of Syk tyrosine kinase in peripheral T-cell lymphomas

“…Recently, a t(5;9)(q33;q22) translocation 2 was reported in a subgroup of PTCL with follicular involvement, 3 resulting in overexpression of the SYK gene under the control of the ITK promoter. SYK encodes a cytoplasmic PTK, which is important in proliferation and prosurvival signaling [4][5][6][7] and is expressed in a variety of hematopoietic cells, including normal B lymphocytes 8 and most B-cell lymphomas. 5,[9][10][11][12] Normal peripheral T cells, however, generally lack Syk protein expression.…”

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).…”