Genomic and expression profiling identifies the B‐cell associated tyrosine kinase Syk as a possible therapeutic target in mantle cell lymphoma

Rinaldi, Andrea; Kwee, Ivo; Taborelli, Monica; Largo, Cristina; Uccella, Silvia; Martin, Vittoria; Poretti, Giulia; Gaïdano, Gianluca; Calabrese, Giuseppe; Martinelli, Giovanni; Baldini, Luca; Pruneri, Giancarlo; Capella, Carlo; Zucca, Emanuele; Cotter, Finbarr E.; Cigudosa, Juan C.; Catapano, Carlo V.; Tibiletti, Maria Grazia; Bertoni, Francesco

doi:10.1111/j.1365-2141.2005.05883.x

Cited by 176 publications

(136 citation statements)

References 54 publications

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“…SYK has recently emerged as a potential new molecular target for the treatment of B-lineage leukemias and lymphomas (29)(30)(31)(32)(33)(34). Compelling evidence from gene profiling studies indicates that abundant STAT3 expression in ALL is associated with chemotherapy and steroid resistance (35)(36)(37).…”

Section: Syk Plays a Pivotal Role In Os-induced Activation Of Stat3 Imentioning

confidence: 99%

STAT3 is a substrate of SYK tyrosine kinase in B-lineage leukemia/lymphoma cells exposed to oxidative stress

Uckun

Qazi

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

127

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We provide unprecedented genetic and biochemical evidence that the antiapoptotic transcription factor STAT3 serves as a substrate for SYK tyrosine kinase both in vitro and in vivo. Induction of SYK in an ecdysone-inducible mammalian expression system results in STAT3 activation, as documented by tyrosine phosphorylation and nuclear translocation of STAT3, as well as amplified expression of several STAT3 target genes. STAT3 activation after oxidative stress (OS) is strongly diminished in DT40 chicken B-lineage lymphoma cells rendered SYK-deficient by targeted disruption of the syk gene. Introduction of a wild-type, C-terminal or N-terminal SH2 domain-mutated, but not a kinase domain-mutated, syk gene into SYK-deficient DT40 cells restores OS-induced enhancement of STAT-3 activity. Thus, SYK plays an important and indispensable role in OS-induced STAT3 activation and its catalytic SH1 domain is critical for this previously unknown regulatory function. These results provide evidence for the existence of a novel mode of cytokineindependent cross-talk that operates between SYK and STAT3 pathways and regulates apoptosis during OS. We further provide experimental evidence that SYK is capable of associating with and phosphorylating STAT3 in human B-lineage leukemia/lymphoma cells challenged with OS. In agreement with a prerequisite role of SYK in OS-induced STAT3 activation, OS does not induce tyrosine phosphorylation of STAT3 in SYK-deficient human proB leukemia cells. Notably, inhibition of SYK with a small molecule drug candidate prevents OS-induced activation of STAT3 and overcomes the resistance of human B-lineage leukemia/lymphoma cells to OSinduced apoptosis.apoptosis | cancer | radiation

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Section: Syk Plays a Pivotal Role In Os-induced Activation Of Stat3 Imentioning

confidence: 99%

STAT3 is a substrate of SYK tyrosine kinase in B-lineage leukemia/lymphoma cells exposed to oxidative stress

Uckun

Qazi

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

127

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“…Thus, antigen-independent phosphorylation of Syk at Y352 or Y525/526 has been observed in follicular lymphoma, diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma. [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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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The protein kinase Syk is a key mediator of proximal B-cell receptor (BCR) signaling. Following antigen stimulation, Syk is recruited to the BCR and becomes activated by phosphorylation at Y352. Recently, Syk was found to be constitutively phosphorylated in several common B-cell lymphoma subtypes, indicating a role for antigen-independent Syk activation in the pathogenesis of these diseases. We now report that Syk is constitutively phosphorylated on the activating Y352 residue in chronic lymphocytic leukemia (CLL) B cells. To examine the effects of constitutive Syk activity on intracellular signaling and leukemic cell survival, we performed in vitro studies with the Syk inhibitor R406. Treatment with R406 induced leukemic cell apoptosis in the majority of investigated cases and affected the basal activity or expression of several pro-survival molecules regulated by Syk, including the Akt and extracellular signalregulated (ERK) kinases, and the anti-apoptotic protein Mcl-1. In addition, R406 prevented the increase in leukemic cell viability induced by sustained BCR engagement and inhibited BCR-induced Akt activation and Mcl-1 upregulation. Collectively, these data identify Syk as a potential target for CLL treatment and suggest that inhibition of this kinase could provide a double therapeutic benefit by disrupting both antigen-dependent and antigen-independent signaling pathways that regulate leukemic cell survival.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Syk tyrosine kinase in peripheral T-cell lymphomas

Feldman,

Sun,

Law

et al. 2008

Leukemia

131

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Peripheral T-cell lymphomas (PTCLs) are fatal in the majority of patients and novel treatments, such as protein tyrosine kinase (PTK) inhibition, are needed. The recent finding of SYK/ITK translocations in rare PTCLs led us to examine the expression of Syk PTK in 141 PTCLs. Syk was positive by immunohistochemistry (IHC) in 133 PTCLs (94%), whereas normal T cells were negative. Western blot on frozen tissue (n ¼ 6) and flow cytometry on cell suspensions (n ¼ 4) correlated with IHC results in paraffin. Additionally, western blot demonstrated that Syk-positive PTCLs show tyrosine (525/526) phosphorylation, known to be required for Syk activation. Fluorescence in situ hybridization showed no SYK/ITK translocation in 86 cases. Overexpression of Syk, phosphorylation of its Y525/526 residues and the availability of orally available Syk inhibitors suggest that Syk merits further evaluation as a candidate target for pharmacologic PTK inhibition in patients with PTCL.

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Genomic and expression profiling identifies the B‐cell associated tyrosine kinase Syk as a possible therapeutic target in mantle cell lymphoma

Cited by 176 publications

References 54 publications

STAT3 is a substrate of SYK tyrosine kinase in B-lineage leukemia/lymphoma cells exposed to oxidative stress

STAT3 is a substrate of SYK tyrosine kinase in B-lineage leukemia/lymphoma cells exposed to oxidative stress

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

Overexpression of Syk tyrosine kinase in peripheral T-cell lymphomas

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