Normal Syk protein level but abnormal tyrosine phosphorylation in B-CLL cells

Sémichon, Monique; Merle-Béral, Hélène; Lang, V. S.; Bismuth, Georges

doi:10.1038/sj.leu.2400832

Cited by 45 publications

(44 citation statements)

References 11 publications

(7 reference statements)

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“…The molecular origin of activatedsignaling pathways found in mature B-cell neoplasms, including B-CLL, is still unclear. Constitutive phosphorylation of Syk has been reported in B-CLL cells (Semichon et al, 1997;Lanham et al, 2003;Deglesne et al, 2006), and in B-cell lymphoma (Leseux et al, 2006;Chen et al, 2008). A ligand-independent BCR signaling, also called tonic signaling (Monroe, 2006), has been recently involved in the constitutive activation of Syk found in B-cell lymphoma (Chen et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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“…(9)(10)(11)34). The protein tyrosine kinase, Syk, has been found to be decreased in only a limited subset of these CLL cells (10,11). Reduced tyrosine phosphorylation of B29 and mb1 also has been reported in leukemic B cells of CLL patients (10).…”

Section: Methodsmentioning

confidence: 99%

“…These data suggest that this phenotype may not result from a dominant negative effect by the B29.18 mutation, but this issue remains to be fully resolved. (9)(10)(11)34). The protein tyrosine kinase, Syk, has been found to be decreased in only a limited subset of these CLL cells (10,11).…”

Section: Methodsmentioning

confidence: 99%

“…Increased Bcl2 expression has been shown to protect B cells against apoptosis in a transgenic mouse (7,8) and could prolong B cell survival, leading to the peripheral accumulation of noncycling B cells in CLL. Impaired B-cell receptor (BCR) signaling has been documented in CLL B cells (9)(10)(11). Altered Src family (11) or Syk (10) tyrosine kinase function may contribute to the decreased protein tyrosine phosphorylation and calcium flux exhibited by selected CLL B cell populations (9).…”

mentioning

confidence: 99%

“…Impaired B-cell receptor (BCR) signaling has been documented in CLL B cells (9)(10)(11). Altered Src family (11) or Syk (10) tyrosine kinase function may contribute to the decreased protein tyrosine phosphorylation and calcium flux exhibited by selected CLL B cell populations (9). However, none of these defects are likely to account for the reduction in surface BCR that is a hallmark of CLL.…”

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confidence: 99%

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Aberrant B cell receptor signaling fromB29(Igβ,CD79b) gene mutations of chronic lymphocytic leukemia B cells

Gordon¹,

Kato²,

Lansigan³

et al. 2000

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

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Chronic lymphocytic leukemia (CLL) B cells characteristically exhibit low or undetectable surface B cell receptor (BCR) and diminished responses to BCR-mediated signaling. These features suggest that CLL cells may have sustained mutations affecting one or more of the BCR proteins required for receptor surface assembly and signal transduction. Loss of expression and mutations in the critical BCR protein B29 (Ig␤, CD79b), are prevalent in CLL and could produce the hallmark features of these leukemic B cells. Because patient CLL cells are intractable to manipulation, we developed a model system to analyze B29 mutations. Jurkat T cells stably expressing , , and mb1 efficiently assembled a functional BCR when infected with recombinant vaccinia virus bearing wild-type B29. In contrast, a B29 CLL mutant protein truncated in the transmembrane domain did not associate with or mb1 at the cell surface. Another B29 CLL mutant lacking the C-terminal immunoreceptor tyrosine activation motif tyrosine and distal residues brought the receptor to the surface as well as wild-type B29 but showed significant impairment in anti-IgM-stimulated signaling events including mitogen-activated protein kinase activation. These findings demonstrate that B29 mutations previously identified in CLL patients can affect BCR-dependent signaling and may contribute to the unresponsive B cell phenotype in CLL. Finally, the features of the B29 mutations in CLL predict that they may be generated by somatic hypermutation. C hronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, but the genetic events leading to this disease remain unknown. CLL patients typically accumulate CD5 ϩ , nonresponsive, growth-arrested B cells that express little or no surface Ig. CLL is unique among B cell malignancies: although multiple chromosomal abnormalities exist in Ϸ50% of all patients (1), no single translocation predominates. Trisomy 12 and deletions of chromosome 13 (13q14) each occur in 20-30% of CLL patients, but these lesions are seen in only a portion of a patient's B cells, indicating that they likely are secondary events (2-4). Deletions in p53 occur late in CLL in a minority of patients and correlate with aggressive transformation (5). Bcl2 expression is elevated in CLL B cells in the absence of Bcl2 gene rearrangements (5) and is correlated with promoter hypomethylation (6). Increased Bcl2 expression has been shown to protect B cells against apoptosis in a transgenic mouse (7,8) and could prolong B cell survival, leading to the peripheral accumulation of noncycling B cells in CLL. Impaired B-cell receptor (BCR) signaling has been documented in CLL B cells (9-11). Altered Src family (11) or Syk (10) tyrosine kinase function may contribute to the decreased protein tyrosine phosphorylation and calcium flux exhibited by selected CLL B cell populations (9). However, none of these defects are likely to account for the reduction in surface BCR that is a hallmark of CLL.B29 and the associated transmembrane protein mb1 are crucial for the a...

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Atomic force microscopy of chronic lymphatic leukaemia cells activation induced by Staphylococcus aureus

Dong

Wang

Sun

et al. 2013

Cell Biology International

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Activation of lymphatic cells is associated with changes in morphology, ultrastructure and adhesion force. We have investigated the activation efficiency of Staphylococcus aureus (SAC) on B-cell chronic lymphatic leukaemia (B-CLL) cells using atomic force microscopy (AFM), and found changes in the above properties. Cell viability and proliferation were measured using Cell Counting Kit-8 (CCK-8) and enzyme-linked immunosorbent assay (ELISA). AFM clearly showed that the volume and nuclear-cytoplasm ratio of cells increased significantly with activated time. It also showed that pseudopodia and immunological synapses began to appear at 24 h. In the activation process, nano-structures of the cell surface became aggregated, and adhesion increased. In conclusion, the results indicate a close relationship between membrane reconstruction and multiplication process of B-CLL cells.

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Normal Syk protein level but abnormal tyrosine phosphorylation in B-CLL cells

Abstract: ily, 13 after binding of its tandem Src homology-2 (SH2)

Cited by 45 publications

References 11 publications

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

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

Aberrant B cell receptor signaling fromB29(Igβ,CD79b) gene mutations of chronic lymphocytic leukemia B cells

Atomic force microscopy of chronic lymphatic leukaemia cells activation induced by Staphylococcus aureus

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