Loss of bHLH transcription factor E2A activity in primary effusion lymphoma confers resistance to apoptosis

Lietz, Andreas; Janz, Martin; Sigvardsson, Mikael; Jundt, Franziska; Dörken, Bernd; Mathas, Stephan

doi:10.1111/j.1365-2141.2007.06583.x

Cited by 13 publications

(13 citation statements)

References 41 publications

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“…Second, we identified an Id2-mediated disruption of the T cell-specific gene expression program in ALCL. Also, the Id2-mediated loss of E2A activity might be linked to tumor progression, because E2A acts as a tumor suppressor in the lymphoid compartment (30,31). Third, the tyrosine kinase receptor for CSF1 (CSF1R) is expressed in ALCL cells at an unusual high level.…”

Section: Discussionmentioning

confidence: 99%

Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma

Mathas

Kreher

Meaburn

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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101

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Although the identification and characterization of translocations have rapidly increased, little is known about the mechanisms of how translocations occur in vivo. We used anaplastic large cell lymphoma (ALCL) with and without the characteristic t(2;5)(p23;q35) translocation to study the mechanisms of formation of translocations and of ALCL transformation. We report deregulation of several genes located near the ALCL translocation breakpoint, regardless of whether the tumor contains the t(2;5). The affected genes include the oncogenic transcription factor Fra2 (located on 2p23), the HLH protein Id2 (2p25), and the oncogenic tyrosine kinase CSF1-receptor (5q33.1). Their up-regulation promotes cell survival and repression of T cellspecific gene expression programs that are characteristic for ALCL. The deregulated genes are in spatial proximity within the nuclear space of t(2;5)-negative ALCL cells, facilitating their translocation on induction of double-strand breaks. These data suggest that deregulation of breakpoint-proximal genes occurs before the formation of translocations, and that aberrant transcriptional activity of genomic regions is linked to their propensity to undergo chromosomal translocations. Also, our data demonstrate that deregulation of breakpoint-proximal genes has a key role in ALCL.cancer genetics ͉ signal transduction ͉ nuclear architecture ͉ lymphomatoid papulosis B alanced chromosomal translocations are a hallmark of cancer cells, and are thought to be important, if not causal, for hematopoietic and mesenchymal tumorigenesis (1). At the molecular level, translocations generally result in either altered expression of genes located directly at a breakpoint, or in fusion of genes located at the 2 breakpoints (1). In most cases, the affected genes are transcription factors or tyrosine kinases, and the translocation generally leads to their inactivation or constitutive activation. This defect often causes inhibition of differentiation or uncontrolled proliferation. Nevertheless, translocations are, at least in some cases, not sufficient to fully transform cells, because chromosomal disease-associated translocations are present in healthy individuals (2), and transgenic mice expressing known tumor fusion proteins do not spontaneously develop tumors in most cases (1, 2).The translocation t(2;5)(p23;q35) is characteristic for anaplastic large cell lymphoma (ALCL), a subgroup of peripheral T cell lymphomas (TCL) (3, 4). By fusion of the 5Ј oligomerization domain of the nucleophosmin (NPM1) gene (located on 5q35) with the 3Ј anaplastic lymphoma kinase (ALK) tyrosine kinase domain (2p23), this translocation results in a NPM-ALK fusion protein with constitutive activation of the ALK kinase (3). Several questions regarding the pathogenesis of ALCL are unresolved. First, in Ϸ40% of systemic ALCL, the translocation t(2;5) is not present (4), suggesting yet unknown alternative mechanisms of transformation. Second, the expression of NPM-ALK per se might not be sufficient for malignant transformation to ALC...

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Section: Discussionmentioning

confidence: 99%

Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma

Mathas

Kreher

Meaburn

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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101

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“…PEL samples are also found to lose E protein activity, partly due to the upregulation of Id2 and ABF-1. E2A overexpression leads to induction of apoptosis, suggesting an Id-mediated oncogenic function that suppresses E protein activity [79].…”

Section: Oncogenic Roles Of Id Proteins In B Cell Lymphomasmentioning

confidence: 99%

Paradoxical role of Id proteins in regulating tumorigenic potential of lymphoid cells

Roy

Zhuang

2018

Front. Med.

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A family of transcription factors known as Id proteins, or inhibitor of DNA binding and differentiation, is capable of regulating cell proliferation, survival and differentiation, and is often upregulated in multiple types of tumors. Due to their ability to promote self-renewal, Id proteins have been considered as oncogenes, and potential therapeutic targets in cancer models. On the contrary, certain Id proteins are reported to act as tumor suppressors in the development of Burkitt's lymphoma in humans, and hepatosplenic and innate-like T cell lymphomas in mice. The contexts and mechanisms by which Id proteins can serve in such contradictory roles to determine tumor outcomes are still not well understood. In this review, we explore the roles of Id proteins in lymphocyte development and tumorigenesis, particularly with respect to inhibition of their canonical DNA binding partners known as E proteins. Transcriptional regulation by E proteins, and their antagonism by Id proteins, act as gatekeepers to ensure appropriate lymphocyte development at key checkpoints. We re-examine the derailment of these regulatory mechanisms in lymphocytes that facilitate tumor development. These mechanistic insights can allow better appreciation of the context-dependent roles of Id proteins in cancers and improve considerations for therapy.

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“…The cloned plasmids were purified with Quiaprep Spin Miniprep Kit (Qiagen) and sequenced using BigDye Terminator v1.1 Cycle Sequencing Kit and ABI Prism 310 Genetic Analyzer (both from Applied Biosystems, Warrington, UK). Clones (5)(6)(7)(8) were sequenced from each sample. The methylation intensity was expressed as percent of methylated CpGs and shown by color coding.…”

Section: Letters To the Editormentioning

confidence: 99%

“…3 Indeed, ABF-1 expression was found to be limited to lymphoblastoid cell lines (LCL), 5 cHL 3 and primary effusion lymphoma. 6 We therefore hypothesized that stable downregulation ABF-1 expression in FL, DLBCL and BL might endow a selective advantage to these tumors. Along with genomic mutations robust and stable gene inactivation has been shown to be achieved by epigenetic gene silencing.…”

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confidence: 99%

ABF-1 is frequently silenced by promoter methylation in follicular lymphoma, diffuse large B-cell lymphoma and Burkitt's lymphoma

et al. 2008

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Loss of bHLH transcription factor E2A activity in primary effusion lymphoma confers resistance to apoptosis

Cited by 13 publications

References 41 publications

Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma

Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma

Paradoxical role of Id proteins in regulating tumorigenic potential of lymphoid cells

ABF-1 is frequently silenced by promoter methylation in follicular lymphoma, diffuse large B-cell lymphoma and Burkitt's lymphoma

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