CD5-induced apoptosis of B cells in some patients with chronic lymphocytic leukemia

Pers, J.-O.; Berthou, Christian; Porakishvili, Nino; Burdjanadze, M; Calvez, Geneviève Le; Jf, Abgrall; Lydyard, PM; Youinou, Pierre; Jamin, C

doi:10.1038/sj.leu.2402327

Cited by 32 publications

(30 citation statements)

References 43 publications

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“…In support of this, CD5 ligation induced apoptosis in a CLL subgroup, possibly by uncoupling CD5 from the BCR or from BCR-associated signaling molecules. 36 We have been able to silence gene expression in CLL with a fairly good efficiency. This technology will allow us to study the role of selected molecules, upstream of p38 MAPK on the survival of malignant cells.…”

Section: Discussionmentioning

confidence: 92%

High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia

et al. 2006

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Chronic lymphocytic leukemia (CLL)-B-cells are quiescent differentiated cells that produce interleukin (IL)-10 and accumulate due to resistance to apoptosis. The mechanisms underlying such resistance are poorly understood. Herein we show that all CLL B-cells tested (30/30) display high mRNA and protein expression of the tumor suppressor Mda-7/IL-24, an IL-10 family member, in comparison to normal B cells. A downstream Mda-7 signaling target, p38 mitogen-activated protein kinase (MAPK) was highly phosphorylated in all CLL cells but not in normal B-cells. Mda-7 expression and p38 MAPK phosphorylation diminished in culture and the latter could be reinduced by recombinant (r)-IL-24 or LPS and Mda-7 transfection. Mda-7/IL-24 siRNA specifically inhibited p38 MAPK phosphorylation in CLL without affecting p38 MAPK, bcl2, or Lyn expression, further demonstrating the direct role of Mda-7/ IL-24 in p38 MAPK activation. Both pharmacological inhibition of p38 MAPK and Mda-7 silencing augmented spontaneous apoptosis by three-fold in CLL cells cultured in autologous serum, which was reversed by LPS and r-IL-24. We established the role of p38 MAPK in CLL cell survival and demonstrated a paradoxical effect, whereby Mda-7 and IL-24, inducers of apoptosis in diverse cancer cells, promote the survival of CLL B-cells through p38 MAPK activation.

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Section: Discussionmentioning

confidence: 92%

High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia

et al. 2006

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“…As a result, some TR-CD5 molecules are synthesized, and eventually degraded in proteasome (35). This results in the enhancement of membrane CD5 expression (36). There is also evidence to suggest that CD5 is involved in promoting survival.…”

Section: Discussionmentioning

confidence: 98%

Selection of the Alternative Exon 1 from thecd5Gene Down-Regulates Membrane Level of the Protein in B Lymphocytes

Garaud¹,

Dantec²,

Berthou³

et al. 2008

The Journal of Immunology

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The human cd5 gene has two alternative exons 1: exon 1A (E1A) which encodes the full-length (FL) CD5 protein and exon 1B (E1B) which encodes a truncated (TR) isoform. The FL variant of CD5 protein is translocated to the plasma membrane, while its TR variant is retained in the cytoplasm. Because there is an inverse relationship between the levels of FL-CD5 and TR-CD5 in B cells, we have addressed the issue of how the selection of exon 1 is determined. In leukemic B cells, DNA methyltransferase (DNMT)1-induced methylation of E1B prevents its transcription. Furthermore, the level of mRNA for DNMT1 correlates inversely with that of mRNA for CD5-E1B. However, suppression of E1B transcription is incomplete, and some molecules of TR-CD5 continue to be synthesized. Bortezomid-induced inhibition of the proteasome establishes that these TR-CD5 molecules are cleared through the ubiquitin-proteasome pathway. Transfection of CD5 mutants into COS-1 cells locates the ubiquitin-binding site at the second destruction box of the extracellular region of CD5. Activation of the B cells by anti-IgM, Staphylococcus aureus Cowan I (SAC), or PMA up-regulates DNMT1, and thereby CD5-E1A mRNA at the expense of CD5-E1B mRNA. Aberrant synthesis of TR-CD5 is thus offset by balanced degradation of excessive protein. Dysregulation of these mechanisms reduces the expression level of membrane CD5, and thereby diminishes the threshold of the response by cells expressing CD5.

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“…Apoptosis was confirmed by cell morphology, enumeration of hypoploid cells and DNA fragmentation analysis, using methods that we have previously described. 3,4 Immunoprecipitation and Western blotting Two aliquots of 1.5 Â 10 7 cells were left on ice for 30 min: the first one was incubated with 15 mg/ml UCHT2 F(ab') 2 and the second with medium alone. Both were washed and warmed to 371C for 5 min.…”

Section: Determination Of Apoptosismentioning

confidence: 99%

“…The patients were classified into those resistant and those sensitive to CD5-triggered apoptosis. 4 At that time, we were unable to identify the reasons for such differences in the responses.…”

Section: Introductionmentioning

confidence: 98%

Role of B-cell antigen receptor-associated molecules and lipid rafts in CD5-induced apoptosis of B CLL cells

Renaudineau¹,

Nédellec²,

Berthou³

et al. 2004

Leukemia

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A total of 40 patients with B-CLL were investigated for CD5-triggered apoptosis and categorized as 20 resistant (group I) and 20 sensitive patients (group II). The densities of surface IgM (sIgM) and CD5 were lower in group I than group II, as were the percentages of CD79b þ , CD38 þ , and Zap70-expressing B cells. CD5 signaling was mediated through the BCR in group II B cells, as established by coimmunoprecipitation of CD5 and CD79a and tyrosine phosphorylation of CD79a. Following colocalization of CD5 and sIgM in membrane lipid rafts (LRs), Syk became associated with these molecules, whereas SHP-1 was uncoupled from CD5. Nonresponsiveness to CD5 crosslinking in group I was ascribed to three possible abnormalities, and defined as three subgroups of patients. In subgroups Ia and Ib, CD5 and sIgM colocalized within the LRs. SHP-1 remained attached to the BCR in subgroup Ia, but not in subgroup Ib, where signal transduction was associated with an excess of truncated CD79b. In subgroup Ic, CD5 and sIgM segregated into different LRs, resulting in no signaling of apoptosis.

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CD5-induced apoptosis of B cells in some patients with chronic lymphocytic leukemia

Cited by 32 publications

References 43 publications

High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia

High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia

Selection of the Alternative Exon 1 from thecd5Gene Down-Regulates Membrane Level of the Protein in B Lymphocytes

Role of B-cell antigen receptor-associated molecules and lipid rafts in CD5-induced apoptosis of B CLL cells

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