Rel A Is an Independent Biomarker of Clinical Outcome in Chronic Lymphocytic Leukemia

Hewamana, Saman; Lin, T; Rowntree, Clare; Karunanithi, Kamaraj; Pratt, Guy; Hills, Robert Kerrin; Fegan, Christopher; Brennan, Paul; Pepper, Chris

doi:10.1200/jco.2008.19.1114

Cited by 51 publications

(51 citation statements)

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“…Recently, nuclear p65 (Rel A) expression has been reported in circulating CLL/SLL. 7 Discrepancies with our study could be related to the different methods used for detecting NF-kB subunits or to the different expression levels of the NF-kB subunits in circulating lymphocytes compared with PCs.…”

mentioning

confidence: 63%

Proliferation centers in chronic lymphocytic leukemia: the niche where NF-κB activation takes place

Herreros

Rodríguez‐Pinilla

Pajares³

et al. 2010

Leukemia

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mentioning

confidence: 63%

Proliferation centers in chronic lymphocytic leukemia: the niche where NF-κB activation takes place

Herreros

Rodríguez‐Pinilla

Pajares³

et al. 2010

Leukemia

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“…CLL cells have been shown to have high constitutive activation of NF-κB (4,28), and the Rel A subunit has independent prognostic value (29). Furthermore, Bcl-2 family proteins are downstream transcriptional targets of NF-κB (30,31), so it seems possible that NF-κB activation might provide a common mechanism for the maintenance and growth of the leukemic clone in CLL.…”

Section: Introductionmentioning

confidence: 99%

Interaction with Vascular Endothelium Enhances Survival in Primary Chronic Lymphocytic Leukemia Cells via NF-κB Activation andDe novoGene Transcription

et al. 2010

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Chronic lymphocytic leukemia (CLL) cells rapidly undergo apoptosis in vitro, suggesting that the in vivo microenvironment provides crucial antiapoptotic signals. Overexpression of the antiapoptotic proteins Bcl-2 and Mcl-1 is a hallmark of CLL, and their expression is further enhanced in the lymphoid tissues. However, the high levels of Mcl-1 found in peripheral blood samples, coupled with its short half-life, led us to hypothesize that it must be actively maintained in the peripheral circulation. Coculture of CLL cells with human vascular endothelial cells significantly enhanced tumor cell survival, an effect that was not observed with normal B cells. This was associated with elevated levels of the antiapoptotic proteins Bcl-2, Mcl-1, and Bcl-X L and marked increased expression of CD38 and CD49d, both of which are associated with clinically aggressive disease. Because CD38, CD49d, and some Bcl-2 family genes are transcriptional targets for NF-κB, we assessed NF-κB activation following coculture with endothelial cells. DNA binding of the NF-κB subunit Rel A was significantly increased and strongly correlated with changes in transcription of CD38, CD49d, BCL2, MCL1, and BCLXL, effects that were reversed by a peptide inhibitor of Rel A. These effects were not observed following coculture with nonendothelial cell lines. Therefore, CLL cells receive specific survival signals following interaction with endothelial cells mediated through the activation of NF-κB and the induction of downstream target genes. This type of interaction in the peripheral vasculature may explain the constitutive NF-κB activation and the overexpression of Bcl-2 family proteins commonly seen in this disease.

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Section: Discussionmentioning

confidence: 79%

“…That NF-B plays a role in the regulation of Mcl-1 expression in CLL cells can be further interpreted in the light of other studies showing the importance of NF-B activation in disease prognosis and in malignant cell resistance to chemotherapeutic agents. 48,49 When taken together with the results of the present work, these studies suggest that the proapoptotic effects of NF-B inhibitors on CLL cells will, at least partly, be mediated by a reduction in Mcl-1 expression.Active NF-B is known to induce the autocrine expression of cytokines, such as IL-6, 20 and overexpression of IL-6 in CLL is associated with adverse disease features and reduced survival. 4 Our results show that CLL cells secrete IL-6 in culture and that both imatinib and BAY11-7082 inhibit this secretion.…”

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confidence: 79%

c-Abl regulates Mcl-1 gene expression in chronic lymphocytic leukemia cells

Allen

Talab

Zuzel

et al. 2011

Blood

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IntroductionChronic lymphocytic leukemia (CLL) is a malignant disease characterized by the gradual accumulation of mature, nonproliferative B cells expressing a distinctive group of surface markers, including CD19, CD23, and CD5. 1,2 It is a heterogeneous disease that can follow an indolent or aggressive course, and understanding the nature of this heterogeneity is an area of intense research interest. 2 CLL cells are resistant to apoptosis, and this is thought to be regulated by survival signals from the microenvironment coupled with intrinsic defects in apoptotic machinery. [3][4][5][6][7] Therefore, understanding in greater detail the molecular basis of such apoptotic resistance may help lead to the discovery of agents effective in CLL treatment.The more aggressive, poor prognostic course of CLL positively correlates with a series of cellular markers, such as ZAP70, CD38, and unmutated IgV H . [8][9][10] Recently, it has been reported that high expression levels of the antiapoptotic protein Mcl-1 in CLL cells correlate with both poor disease prognosis 11 and in vitro and in vivo chemoresistance. [11][12][13][14] Moreover, down-regulation of Mcl-1 using antisense oligonucleotides results in cell death during in vitro culture, 15 and elevated Mcl-1 protein expression has been shown to prolong the survival of CLL cells exposed to a variety of apoptosis-inducing stimuli. 16 Taken together, this evidence establishes Mcl-1 as a critical mediator of CLL cell survival.Another signaling protein overexpressed in CLL cells that plays a role in apoptotic resistance is the nonreceptor tyrosine kinase c-Abl. 17 c-Abl appears to be important for normal B-cell development because targeted disruption of the gene encoding this protein in mice results in development of lymphopenia. 18 c-Abl functions in B cells to phosphorylate CD19 after antigen engagement of the B-cell receptor (BCR), highlighting c-Abl as an important regulator of B-cell signaling. 19 In CLL, the overexpression of c-Abl stimulates activity of the nuclear factor-B (NF-B) pathway, leading to increased resistance of the malignant cells to spontaneous apoptosis. 17 Thus, a pathophysiologic role for this kinase in CLL is in the regulation of prosurvival signaling.Active NF-B is known to induce the autocrine expression of cytokines, such as interleukin-6 (IL-6). 20 IL-6 in CLL is associated with adverse disease features and reduced patient survival. 4 It is thought that elevated levels of IL-6 can promote disease progression either indirectly through effects on the microenvironment or directly through effects on cell survival and proliferation. An example of the direct effect of IL-6 is its capability of activating the transcription factor STAT3 via the classic IL-6 receptor (IL-6R) pathway. 21 Such stimulation of STAT3 then promotes up-regulation of antiapoptotic genes, such as Mcl-1. [22][23][24] A role for c-Abl in the activation of STAT3 has been described, 25 as well as a connection, in chronic myelogeneous leukemia (CML) cells, between c-Abl and Mcl-1. 21 Th...

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Rel A Is an Independent Biomarker of Clinical Outcome in Chronic Lymphocytic Leukemia

Abstract: Rel A is an independent prognostic marker of survival in CLL and seems to have the unique capacity to predict the duration of response to therapy. Prospective assessment of Rel A as a marker of clinical outcome and as a therapeutic target are now warranted.

Cited by 51 publications

References 32 publications

Proliferation centers in chronic lymphocytic leukemia: the niche where NF-κB activation takes place

Proliferation centers in chronic lymphocytic leukemia: the niche where NF-κB activation takes place

Interaction with Vascular Endothelium Enhances Survival in Primary Chronic Lymphocytic Leukemia Cells via NF-κB Activation andDe novoGene Transcription

c-Abl regulates Mcl-1 gene expression in chronic lymphocytic leukemia cells

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