The IKK2/NF-κB pathway suppresses MYC-induced lymphomagenesis

Klapproth, Kay; Sander, Sandrine; Marinković, Dragan; Baumann, Bernd; Wirth, Thomas

doi:10.1182/blood-2008-09-181008

Cited by 51 publications

(72 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This would be consistent with work indicating that high-level c-Myc expression inhibits NF-B activity and with the notion that Myc-driven tumors such as Burkitt's lymphoma are poorly immunogenic, due to low-level NF-B activity, compared to diffuse large B cell lymphomas (DLBCLs) or LCLs (9,12,25). Therefore, a set of c-Myc targets may be responsible in part for low LMP1 levels.…”

Section: Discussionsupporting

confidence: 88%

Analysis of Epstein-Barr Virus-Regulated Host Gene Expression Changes through Primary B-Cell Outgrowth Reveals Delayed Kinetics of Latent Membrane Protein 1-Mediated NF-κB Activation

Price

Tourigny

Forte

et al. 2012

J Virol

130

View full text Add to dashboard Cite

b Epstein-Barr virus (EBV) is an oncogenic human herpesvirus that dramatically reorganizes host gene expression to immortalize primary B cells. In this study, we analyzed EBV-regulated host gene expression changes following primary B-cell infection, both during initial proliferation and through transformation into lymphoblastoid cell lines (LCLs). While most EBV-regulated mRNAs were changed during the transition from resting, uninfected B cells through initial B-cell proliferation, a substantial number of mRNAs changed uniquely from early proliferation through LCL outgrowth. We identified constitutively and dynamically EBV-regulated biological processes, protein classes, and targets of specific transcription factors. Early after infection, genes associated with proliferation, stress responses, and the p53 pathway were highly enriched. However, the transition from early to long-term outgrowth was characterized by genes involved in the inhibition of apoptosis, the actin cytoskeleton, and NF-B activity. It was previously thought that the major viral protein responsible for NF-B activation, latent membrane protein 1 (LMP1), is expressed within 2 days after infection. Our data indicate that while this is true, LCL-level LMP1 expression and NF-B activity are not evident until 3 weeks after primary B-cell infection. Furthermore, heterologous NF-B activation during the first week after infection increased the transformation efficiency, while early NF-B inhibition had no effect on transformation. Rather, inhibition of NF-B was not toxic to EBV-infected cells until LMP1 levels and NF-B activity were high. These data collectively highlight the dynamic nature of EBV-regulated host gene expression and support the notion that early EBV-infected proliferating B cells have a fundamentally distinct growth and survival phenotype from that of LCLs.

show abstract

Section: Discussionsupporting

confidence: 88%

Analysis of Epstein-Barr Virus-Regulated Host Gene Expression Changes through Primary B-Cell Outgrowth Reveals Delayed Kinetics of Latent Membrane Protein 1-Mediated NF-κB Activation

Price

Tourigny

Forte

et al. 2012

J Virol

130

View full text Add to dashboard Cite

show abstract

“…Compared with other aggressive lymphomas, BL tumors lack expression of NF-kB target genes, suggesting that active BCR signaling does not contribute to this malignancy (Dave et al 2006). In fact, MYC transgenic mouse models showed that constitutive NF-kB activity is incompatible with the development of MYC-induced lymphomas (Klapproth et al 2009). The involvement of PI3K signaling in BL pathogenesis was recently supported by analysis of mice engineered to express MYC and a constitutively active form of PI3K specifically in B cells undergoing the GC reaction (Sander et al 2012).…”

Section: Oncogenic Signaling Pathways In Blmentioning

confidence: 99%

Oncogenic Mechanisms in Burkitt Lymphoma

Schmitz

Ceribelli

Pittaluga

et al. 2014

Cold Spring Harbor Perspectives in Medicine

213

174

View full text Add to dashboard Cite

Burkitt lymphoma is a germinal center B-cell-derived cancer that was instrumental in the identification of MYC as an important human oncogene more than three decades ago. Recently, new genomics technologies have uncovered several additional oncogenic mechanisms that cooperate with MYC to create this highly aggressive cancer. The transcription factor TCF-3 is central to Burkitt lymphoma pathogenesis. TCF-3 is rendered constitutively active in Burkitt lymphoma by two related mechanisms: (1) somatic mutations that inactivate its negative regulator ID3, and (2) somatic mutations in TCF-3 that block the ability of ID3 to bind and interfere with its activity as a transcription factor. TCF-3 is also a master regulator of normal germinal center B-cell differentiation. Within the germinal center, TCF-3 up-regulates genes that are characteristically expressed in the rapidly dividing centroblasts, the putative cell of origin for Burkitt lymphoma, while repressing genes expressed in the less proliferative centrocytes. TCF-3 promotes antigen-independent (tonic) B-cell-receptor signaling in Burkitt lymphoma by transactivating immunoglobulin heavy-and light-chain genes while repressing PTPN6, which encodes the phosphatase SHP-1, a negative regulator of Bcell-receptor signaling. Tonic B-cell-receptor signaling sustains Burkitt lymphoma survival by engaging the PI3 kinase pathway. In addition, TCF-3 promotes cell-cycle progression by transactivating CCND3, encoding a D-type cyclin that regulates the G 1 -S phase transition. Additionally, CCND3 accumulates oncogenic mutations that stabilize cyclin D3 protein expression and drive proliferation. These new insights into Burkitt lymphoma pathogenesis suggest new therapeutic strategies, which are sorely needed in developing regions of the world where this cancer is endemic.

show abstract

“…After the blood was drawn, mice were injected intraperitoneally with decitabine (1.0 mg/kg body weight) dissolved in saline (0.9% w/v NaCl) or equal volume of saline. The treatment was given for six doses in a period of two weeks (on days 1, 3,5,8,10,12). The serum level of tartrate resistant acid phosphatase 5b (TRAP5b) was measured by a TRAP enzyme-linked immunosorbent assay (ELISA) kit (BD Biosciences, San Jose, CA, USA) following the manufacturer's instructions.…”

Section: Serum Analysis Of Tartrate-resistant Acid Phosphatase 5b (Trmentioning

confidence: 99%

“…In B cell lymphomas especially Burkitt lymphomas and Follicular lymphomas, decitabine suppressed the transcription program supporting the expression of translocated oncogenes MYC and BCL-2, leading to impaired tumor cell fitness. In Burkitt lymphomas characterized by absence of NF-κB signaling [12], decitabine activated NF-κB, which contributes to its tumor suppressing effects [10].…”

Section: Introductionmentioning

confidence: 99%

Decitabine represses osteoclastogenesis through inhibition of RANK and NF-κB

Guan

et al. 2015

Cellular Signalling

View full text Add to dashboard Cite

The IKK2/NF-κB pathway suppresses MYC-induced lymphomagenesis

Cited by 51 publications

References 49 publications

Analysis of Epstein-Barr Virus-Regulated Host Gene Expression Changes through Primary B-Cell Outgrowth Reveals Delayed Kinetics of Latent Membrane Protein 1-Mediated NF-κB Activation

Analysis of Epstein-Barr Virus-Regulated Host Gene Expression Changes through Primary B-Cell Outgrowth Reveals Delayed Kinetics of Latent Membrane Protein 1-Mediated NF-κB Activation

Oncogenic Mechanisms in Burkitt Lymphoma

Decitabine represses osteoclastogenesis through inhibition of RANK and NF-κB

Contact Info

Product

Resources

About