Homeostatic chemokines increase survival of B-chronic lymphocytic leukemia cells through inactivation of transcription factor FOXO3a

Ticchioni, Michel; Essafi, Makram; Jeandel, P.; Davi, Frédéric; Cassuto, Jill‐Patrice; Deckert, Marcel; Bernard, Alain

doi:10.1038/sj.onc.1210519

Cited by 90 publications

(98 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…44,45 In addition, the Constitutive activation of Syk in B-CLL S Gobessi et al treatment of CLL cells with R406 decreased the basal activity of several downstream signaling molecules that play important roles in regulating CLL-cell survival, such as the Akt, ERK and GSK-3 kinases and the FoxO1/3a transcription factors. 25,26,37,46,47 The specificity of R406 in inhibiting Syk-mediated activation of Akt and ERK was further confirmed in experiments with a constitutively active TEL-Syk protein.…”

Section: Discussionmentioning

confidence: 66%

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

et al. 2008

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 66%

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

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Thus, it is tempting to speculate that CCL19 and CCL21 not only attract CLL cells to LNs, but also promote prosurvival niches inside these SLOs where high concentrations of CCR7 ligands are found. We and others (33) have found that such prosurvival effect is partially dependent on PI3K and MAPKs pathways. Indeed, the strong activation of ERK by both the CCR7 ligands in the experiments of western blot is probably taking account for the anti-apoptotic effects of CCL19/21 opposite to their migratory activities that are not dependent on ERK.…”

Section: Ccl19 and Ccl21 Increase B-cll Cells Survivalmentioning

confidence: 99%

Analysis of migratory and prosurvival pathways induced by the homeostatic chemokines CCL19 and CCL21 in B-cell chronic lymphocytic leukemia

Cuesta-Mateos

López-Giral

Alfonso-Pérez

et al. 2010

Experimental Hematology

View full text Add to dashboard Cite

The CCR7 chemokine receptor has been reported to promote the localization of chronic lymphocytic leukemia (CLL) cells into lymph nodes (LNs) where they may gain survival signals, but the mechanisms mediating these effects are largely unknown. We investigated the role of different signaling pathways in the migratory and prosurvival effects exerted by the chemokines CCL19 and CCL21, the CCR7 ligands, in CLL cells. Their 3

show abstract

“…[3][4][5] This kinase is also activated in response to many other microenvironmental stimuli that increase leukemic cell survival or induce proliferation, including CXCL12, CD40 ligand, IL-4, CpG oligonucleotides, lysophosphatidic acid, high-density lipoprotein particles and contact with bone marrow stromal cells. [6][7][8][9][10][11][12][13] In addition, increased basal Akt activity has been reported in some studies, suggesting that constitutive Akt signaling may contribute to the increased survival of the malignant lymphocytes. In line with this possibility, specific inhibition or downregulation of Akt has been shown to induce apoptosis in freshly isolated CLL cells.…”

Section: Introductionmentioning

confidence: 99%

Reduced expression of the tumor suppressor PHLPP1 enhances the antiapoptotic B-cell receptor signal in chronic lymphocytic leukemia B-cells

et al. 2010

View full text Add to dashboard Cite

The PI3K/Akt pathway is activated in response to various microenvironmental stimuli that regulate the survival and proliferation of chronic lymphocytic leukemia (CLL) B-cells, including triggering of the B-cell receptor (BCR). Although this pathway is frequently targeted in cancer, no significant alterations have yet been identified in CLL. We now show that the phosphatase PH domain leucin-rich repeat protein phosphatase (PHLPP1), a recently identified tumor suppressor and negative regulator of the Akt kinase, is absent or expressed at substantially reduced levels in CLL B-cells. To determine what the consequences of PHLPP1 loss on BCR signaling are, we downregulated or re-expressed PHLPP1 in lymphoma cell lines and primary CLL B-cells, respectively. Downregulation of PHLPP1 increased BCR-induced phosphorylation and activation of the Akt, GSK3 and ERK kinases, whereas re-expression had the opposite effect. Importantly, re-expression of PHLPP1 in primary CLL cells prevented upregulation of Mcl-1 and inhibited the increase in leukemic cell viability induced by sustained BCR engagement. Enforced expression of PHLPP1 also affected the response to other microenvironmental stimuli, particularly in terms of ERK phosphorylation. Collectively, these data show that CLL cells lack an important negative regulator of the Akt and ERK pathways, which could confer them a growth advantage by facilitating the propagation of crucial microenvironment-derived stimuli.

show abstract

Homeostatic chemokines increase survival of B-chronic lymphocytic leukemia cells through inactivation of transcription factor FOXO3a

Cited by 90 publications

References 35 publications

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

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

Analysis of migratory and prosurvival pathways induced by the homeostatic chemokines CCL19 and CCL21 in B-cell chronic lymphocytic leukemia

Reduced expression of the tumor suppressor PHLPP1 enhances the antiapoptotic B-cell receptor signal in chronic lymphocytic leukemia B-cells

Contact Info

Product

Resources

About