A sustained activation of PI3K/NF-κB pathway is critical for the survival of chronic lymphocytic leukemia B cells

Cuní, Sandra; Pérez-Aciego, Paloma; Pérez-Chacón, Gema; Vargas, Juan A.; Sánchez, Antonio; Martín-Saavedra, Francisco M.; Ballester, Sara; García-Marco, José A.; Zurdo, Julia; Durántez, A

doi:10.1038/sj.leu.2403398

Cited by 227 publications

(222 citation statements)

References 67 publications

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“…These results were confirmed by another study, which demonstrated constitutive NF-kB activity in malignant B-lymphocytes of 71 B-CLL patients. 46 Additional studies revealed the importance of supportive interactions with a specific microenvironment for the survival of malignant B-CLL cells. One fundamental NFkB-activatory stimulus in the bone marrow and in neoplastic follicles is mediated by a paracrine interaction between CD40L (on stroma cells) and CD40 (on tumor cells).…”

Section: B-cllmentioning

confidence: 99%

“…These pathways are constitutively activated in B-CLL upon CD40 crosslinking, leading to PI3-K-dependent Akt and NF-kB signaling. 46 Vascular endothelial growth factor (VEGF), another factor of the microenvironment, implicated in increased neo-vascularization in B-CLL bone marrow, has been demonstrated recently to be potentially important for the pathogenesis and prognosis of B-CLL. 47 B-CLL cells produce VEGF in vitro.…”

Section: B-cllmentioning

confidence: 99%

“…49 Furthermore, Bcl-X L expression in B-CLL cells is maintained through NF-kB and the expression of X-chromosome-linked inhibitor of apoptosis protein (XIAP) and FLIP in B-CLL has been linked to the constitutive PI3K-dependent NF-kB activation. 46 ALL B-precursor ALL is associated in 25-30% of adult cases, and 5% of childhood cases with the t(9;22) chromosomal translocation also found in 95% of chronic myeloid leukemia (CML, see below). 50 This leads to the transcription of the Bcr/Abl fusion oncoprotein, a serine threonine kinase that activates NF-kB.…”

Section: B-cllmentioning

confidence: 99%

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Targeting NF-κB in hematologic malignancies

et al. 2006

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The transcription factor nuclear factor kappa B (NF-jB) can intervene in oncogenesis by virtue of its capacity to regulate the expression of a plethora of genes that modulate apoptosis, and cell survival as well as proliferation, inflammation, tumor metastasis and angiogenesis. Different reports demonstrate the intrinsic activation of NF-jB in lymphoid and myeloid malignancies, including preneoplastic conditions such as myelodysplastic syndromes, underscoring its implication in malignant transformation. Targeting intrinsic NF-jB activation, as well as its upstream and downstream regulators, may hence constitute an additional approach to the oncologist's armamentarium. Several small inhibitors of the NF-jB-activatory kinase IjB kinase, of the proteaseome, or of the DNA binding of NF-jB subunits are under intensive investigation. Currently used cytotoxic agents can induce NF-jB activation as an unwarranted side effect, which confers apoptosis suppression and hence resistance to these drugs. Thus, NF-jB inhibitory molecules may be clinically useful, either as single therapeutic agents or in combination with classical chemotherapeutic agents, for the treatment of hematological malignancies.

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Section: B-cllmentioning

confidence: 99%

Section: B-cllmentioning

confidence: 99%

Section: B-cllmentioning

confidence: 99%

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Targeting NF-κB in hematologic malignancies

et al. 2006

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“…[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

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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.

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“…1,2 Activation of the phosphatidylinositol-3-kinase/Akt (PI-3-K/Akt) pathway in CLL cells inhibits apoptotic death. 3 Lipoprotein particles in sera also modulate apoptotic cell death. 4,5 High-density lipoprotein particles, interacting through a sphingosine-1-phosphate receptor 3 (S1P 3 ), inhibit apoptosis by activating the PI-3-K/Akt pathway.…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein E genotype as a determinant of survival in chronic lymphocytic leukemia

et al. 2008

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Survival of chronic lymphocytic leukemia (CLL) cells requires sustained activation of the antiapoptotic PI-3-K/Akt pathway, and many therapies for CLL cause leukemia cell death by triggering apoptosis. Blood lipoprotein particles are either pro-or antiapoptotic. High-density lipoprotein particles are antiapoptotic through sphingosine-1-phosphate receptor 3-mediated activation of the PI-3-K/Akt pathway. Apolipoprotein E4 (apoE4)-very low density lipoproteins (VLDL) increase apoptosis, but the apoE2-VLDL and apoE3-VLDL isoforms do not. As increased B-cell apoptosis favors longer survival of CLL patients, we hypothesized that APOE4 genotype would beneficially influence the clinical course of CLL. We report here that women (but not men) with an APOE4 genotype had markedly longer survival than non-APOE4 patients. VLDL is metabolized to low-density lipoprotein through lipoprotein lipase. Higher levels of lipoprotein lipase mRNA in these CLL patients correlated with shorter survival. The beneficial effect of APOE4 in CLL survival is likely mediated through APOE4 allele-specific regulation of leukemia cell apoptosis. The APOE allele and genotype distribution in these CLL patients is the same as in unaffected control populations, suggesting that although APOE genotype influences CLL outcome and response to therapy, it does not alter susceptibility to developing this disease.

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A sustained activation of PI3K/NF-κB pathway is critical for the survival of chronic lymphocytic leukemia B cells

Cited by 227 publications

References 67 publications

Targeting NF-κB in hematologic malignancies

Targeting NF-κB in hematologic malignancies

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

Apolipoprotein E genotype as a determinant of survival in chronic lymphocytic leukemia

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