Clonal Deleterious Mutations in the Iκbα Gene in the Malignant Cells in Hodgkin's Lymphoma (original) (raw)
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International Journal of Cancer, 2009
A consistent feature of the Hodgkin and Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL) is the constitutive activation of NF-jB transcription factors. In Epstein-Barr virus (EBV)-associated cases of cHL, expression of viral antigens most probably leads to NF-jB activation but for non-EBV-associated cases, the mechanism is not clear. Previous small studies have demonstrated deleterious mutations of NFKBIA, the gene encoding IjBa, in HRS cells. In the present study, we aimed to establish the frequency of NFKBIA mutation in cHL by investigating a larger series of cases and to determine whether these mutations are a characteristic feature of non-EBV-associated cHL. Single HRS cells from 20 cases of cHL were analysed by PCRs covering all 6 exons of the gene. Clonal deleterious mutations were detected in 3 cases and in 1 case both alleles of the gene were shown to harbour mutations. NFKBIA mutations were detected only in non-EBV-associated cases but the majority of these cases had wild-type NFKBIA. It remains possible that defects in genes encoding other inhibitors of NF-jB, such as TNFAIP3 (A20) and CYLD, are involved in the latter cases, as described for one case in this series. ' 2009 UICC Additional Supporting Information may be found in the online version of this article.
Journal of Experimental Medicine, 2001
Gene expression profiling has revealed that diffuse large B cell lymphoma (DLBCL) consists of at least two distinct diseases. Patients with one DLBCL subtype, termed activated B cell-like (ABC) DLBCL, have a distinctly inferior prognosis. An untapped potential of gene expression profiling is its ability to identify pathogenic signaling pathways in cancer that are amenable to therapeutic attack. The gene expression profiles of ABC DLBCLs were notable for the high expression of target genes of the nuclear factor (NF)-B transcription factors, raising the possibility that constitutive activity of the NF-B pathway may contribute to the poor prognosis of these patients. Two cell line models of ABC DLBCL had high nuclear NF-B DNA binding activity, constitutive I B kinase (IKK) activity, and rapid I B ␣ degradation that was not seen in cell lines representing the other DLBCL subtype, germinal center B-like (GCB) DLBCL. Retroviral transduction of a super-repressor form of I B ␣ or dominant negative forms of IKK  was toxic to ABC DLBCL cells but not GCB DLBCL cells. DNA content analysis showed that NF-B inhibition caused both cell death and G1-phase growth arrest. These findings establish the NF-B pathway as a new molecular target for drug development in the most clinically intractable subtype of DLBCL and demonstrate that the two DLBCL subtypes defined by gene expression profiling utilize distinct pathogenetic mechanisms.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2005
The human Burkitt lymphoma Daudi cell line expresses constitutively active nuclear factor kappaB (NF-nB) in the nucleus in spite of high levels of inhibitor kappaB-alpha (InB-a) in the cytoplasm. The antiproliferative response of these cells to interferon-a (IFN-a) correlated with the inhibition of the constitutive NF-nB activity by the cytokine. The present study shows that IFN-a caused an increase in p53 level, inhibited cell proliferation by [ 3 H]thymidine incorporation, and stimulated cytotoxicity and apoptosis by PARP-cleavage in the Daudi cells. In order to study the relationship between the constitutively active NF-nB and InB-a, a dominant negative mutant InB-a (InB-aDN), lacking the N-terminal 36 amino acids required for the activation of NF-nB by tumor necrosis factor-a (TNF-a), was expressed in the Daudi cells. The expression of InB-aDN protein did not inhibit the constitutive NF-nB activity, but it inhibited cell proliferation, antiproliferative response to IFN-a, and phosphorylated mitogen activated protein kinase (p-MAPK) level. Thus, our results suggest that constitutive NF-nB activity in the human Burkitt lymphoma Daudi cells is maintained by a mechanism independent of InB-a degradation, and that the InB-a is involved in the proliferation of these cells, possibly through the MAP kinase pathway. Therefore, in addition to IFN-a treatment, both NF-nB and InB-a may be used as drug targets for inhibiting cell proliferation in the lymphomas.
Journal of Biological Chemistry, 2014
Background: How IκB kinaseβ K171E and K171T mutations mediate lymphomagenesis is not known Results: We performed biochemical, molecular modeling and TALEN-based knockin studies on wild-type and mutant IKKβ Conclusion: Mutant IKKβ molecules are constitutively active in an activation-loop phosphorylation-independent manner Significance: These results have broad implications for the function of positively charged residues in all activation-loop dependent kinases
The human Burkitt lymphoma Daudi cell line expresses constitutively active nuclear factor kappaB (NF-nB) in the nucleus in spite of high levels of inhibitor kappaB-alpha (InB-a) in the cytoplasm. The antiproliferative response of these cells to interferon-a (IFN-a) correlated with the inhibition of the constitutive NF-nB activity by the cytokine. The present study shows that IFN-a caused an increase in p53 level, inhibited cell proliferation by [ 3 H]thymidine incorporation, and stimulated cytotoxicity and apoptosis by PARP-cleavage in the Daudi cells. In order to study the relationship between the constitutively active NF-nB and InB-a, a dominant negative mutant InB-a (InB-aDN), lacking the N-terminal 36 amino acids required for the activation of NF-nB by tumor necrosis factor-a (TNF-a), was expressed in the Daudi cells. The expression of InB-aDN protein did not inhibit the constitutive NF-nB activity, but it inhibited cell proliferation, antiproliferative response to IFN-a, and phosphorylated mitogen activated protein kinase (p-MAPK) level. Thus, our results suggest that constitutive NF-nB activity in the human Burkitt lymphoma Daudi cells is maintained by a mechanism independent of InB-a degradation, and that the InB-a is involved in the proliferation of these cells, possibly through the MAP kinase pathway. Therefore, in addition to IFN-a treatment, both NF-nB and InB-a may be used as drug targets for inhibiting cell proliferation in the lymphomas. D
NF- B is essential for the progression of KSHV- and EBV-infected lymphomas in vivo
Blood, 2006
lymphomas in vivo B is essential for the progression of KSHV-and EBV-infected κ NFhttp://bloodjournal.hematologylibrary.org/content/107/8/3295.full.html Updated information and services can be found at: (1930 articles) Signal Transduction (4217 articles) Neoplasia Articles on similar topics can be found in the following Blood collections http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub\_requests Information about reproducing this article in parts or in its entirety may be found online at: http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#reprints Information about ordering reprints may be found online at: http://bloodjournal.hematologylibrary.org/site/subscriptions/index.xhtml Information about subscriptions and ASH membership may be found online at: Activated NF-B is a critical mechanism by which lymphoma cells infected by Epstein-Barr virus (EBV/HHV-4) and Kaposi sarcoma herpesvirus (KSHV/HHV-8) are protected from apoptotic stress. Selective pharmacologic inhibition of constitutive NF-B activity induces apoptosis in KSHV-and EBV-infected lymphoma cells. In both tumor types, pharmacologic inhibition of NF-B in vitro induced identical mitochondrially mediated apoptosis cascades. Assessment of gene regulation by microarray analysis revealed that the inhi-bition of NF-B in tumor cells results in the down-regulation of a distinct group of prosurvival genes, including cIAP-1, cIAP-2, cFLIP, and IL-6. Using EBV-and KSHV-associated lymphomas in a murine system, we demonstrated that Bay 11-7082, a selective pharmacologic inhibitor of NF-B, prevents or delays tumor growth and prolongs disease-free survival. Inhibition of NF-B activity and tumor growth responses were further documented using a traceable reporter KSHV-positive cell line and in vivo imaging. These find-ings indicate that specific NF-B-regulated survival factors work cooperatively to protect KSHV-and EBV-infected lymphoma cells from apoptosis such that they promote the establishment and progression of KSHVand EBV-associated lymphomas in mice. They also support the use of selective NF-B inhibitors in the treatment of herpesvirusassociated lymphomas. (Blood. 2006;107: 3295-3302)
Modern Pathology, 2014
The activation of nuclear factor kappa B (NFjB) transcription factor family is considered to have a key role in diffuse large B-cell lymphoma (DLBCL) pathogenesis and is associated with a specific molecular subtype, the activated B-cell-like (ABC) subtype. We evaluated the expression of NFjB by immunohistochemistry in a large series of DLBCL cases. The five different NFjB family members (NFjB1, NFjB2, RELA, RELB, and REL) showed a heterogeneous expression pattern with the vast majority of cases being positive for at least one factor. Two independent series of tumor samples were classified into germinal center B-cell-like (GCB) or ABC subtypes using different approaches, immunohistochemistry, or gene expression profiling, and the expression of NFjB family members was assessed. Notably, no significant differences regarding the expression of the different NFjB members were detected between the two subtypes, suggesting that NFjB signaling is a prominent feature not only in the ABC subtype, but also in the GCB tumors. Of the five transcription factors, only REL expression had a significant clinical impact on R-CHOP-treated diffuse large B-cell lymphoma, identifying a subgroup of patients with superior clinical outcome.