Disruption of the MYC-miRNA-EZH2 loop to suppress aggressive B-cell lymphoma survival and clonogenicity

Zhao, Xiaohong; Lwin, Tint; Zhang, Xinwei; Huang, Andy; Wang, Jian; Márquez, Víctor E.; Chen‐Kiang, Selina; Dalton, William S.; Sotomayor, Eduardo M.; Tao, Jianguo

doi:10.1038/leu.2013.94

Cited by 102 publications

(97 citation statements)

References 37 publications

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“…13,16 Intriguingly, the gene profile transcriptionally regulated by MYC varies in different cell types with relatively little overlap. 17 Two recent studies shed light on this puzzling observation, showing that, instead of activating a particular gene signature, MYC acts as an amplifier of the transcribed genes in a given cell by uploading to the promoters of active genes and enhancing their transcription.…”

Section: Myc As a Transcription Factormentioning

confidence: 99%

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Understanding MYC-driven aggressive B-cell lymphomas: pathogenesis and classification

Ott

Rosenwald

Campo

2013

Blood

219

214

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MYC is a potent oncogene initially identified as the target of the t(8;14)(q24;q32) chromosome translocation in Burkitt lymphoma. MYC gene alterations have been identified in other mature B-cell neoplasms that are usually associated with an aggressive clinical behavior. Most of these tumors originate in cells that do not normally express MYC protein. The oncogenic events leading to MYC up-regulation seem to overcome the inhibitory effect of physiological repressors such as BCL6 or BLIMP1.Aggressive lymphomas frequently carry additional oncogenic alterations that cooperate with MYC dysregulation, likely counteracting its proapoptotic function. The development of FISH probes and new reliable antibodies have facilitated the study of MYC gene alterations and protein expression in large series of patients, providing new clinical and biological perspectives regarding MYC dysregulation in aggressive lymphomas. MYC gene alterations in large B-cell lymphomas are frequently associated with BCL2 or BCL6 translocations conferring a very aggressive behavior. Conversely, MYC protein up-regulation may occur in tumors without apparent gene alterations, and its association with BCL2 overexpression also confers a poor prognosis. In this review, we integrate all of this new information and discuss perspectives, challenges, and open questions for the diagnosis and management of patients with MYC-driven aggressive B-cell lymphomas. (Blood. 2013;122(24):3884-3891) Introduction MYC was initially identified as the target oncogene dysregulated by the t(8;14)(q24;q32) translocation in Burkitt lymphoma (BL). MYC rearrangements involving the heavy-and light-chain immunoglobulin (IGL) loci and different non-IG genes were subsequently detected in other lymphoid neoplasms usually associated with very aggressive clinical behavior.1,2 The transforming oncogenic potential of MYC was initially demonstrated in cell lines and transgenic animal models. However, MYC dysregulation alone does not cause lymphoma, 4 and the t(8;14) has been found at very low levels in blood and BM of healthy individuals, 5 indicating that this genetic alteration per se is not sufficient to trigger lymphomagenesis. BL and most lymphomas carrying MYC translocations are among the most proliferative tumors. However, MYC expression has been difficult to identify in the germinal center (GC), the lymphoid cell compartment with the highest proliferative fraction, where most of these tumors originate. Understanding the possible role of MYC in normal lymphoid regulation and particularly the modulation of the GC reaction has been elusive.Recent studies, including basic immunology analyses, new animal models, next-generation sequencing, and clinicopathological observations, are converging to provide a new perspective of the role of MYC in the lymphoid system and the pathogenesis of aggressive lymphomas. In this review, we integrate all of this new information and discuss new perspectives, challenges, and open questions for the diagnosis and management of patients. MYC as a transc...

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Section: Myc As a Transcription Factormentioning

confidence: 99%

“…13,16 Intriguingly, the gene profile transcriptionally regulated by MYC varies in different cell types with relatively little overlap.…”

mentioning

confidence: 99%

Understanding MYC-driven aggressive B-cell lymphomas: pathogenesis and classification

Ott

Rosenwald

Campo

2013

Blood

219

214

View full text Add to dashboard Cite

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“…In acute myelogenous leukemia, BRD4 is essential for tumor maintenance, and JQ1 recapitulates the effects of RNA interference of BRD4 (4,5). JQ1 was subsequently shown to have an antiproliferative effect in other hematological malignancies and solid organ tumors including glioblastoma, prostate cancer, and neuroblastoma (6)(7)(8)(9)(10). The current model of how BET inhibitors (BETi) inhibit tumor cell proliferation places inhibition of MYC as mediating activity in lymphoid tumors, with Myc-independent activity in some solid tumor types such as lung adenocarcinoma (11).…”

mentioning

confidence: 99%

BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma

Bhadury

Nilsson

Muralidharan

et al. 2014

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

199

149

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The bromodomain and extraterminal (BET) domain family of proteins binds to acetylated lysines on histones and regulates gene transcription. Recently, BET inhibitors (BETi) have been developed that show promise as potent anticancer drugs against various solid and hematological malignancies. Here we show that the structurally novel and orally bioavailable BET inhibitor RVX2135 inhibits proliferation and induces apoptosis of lymphoma cells arising in Myctransgenic mice in vitro and in vivo. We find that BET inhibition exhibits broad transcriptional effects in Myc-transgenic lymphoma cells affecting many transcription factor networks. By examining the genes induced by BETi, which have largely been ignored to date, we discovered that these were similar to those induced by histone deacetylase inhibitors (HDACi). HDACi also induced cell-cycle arrest and cell death of Myc-induced murine lymphoma cells and synergized with BETi. Our data suggest that BETi sensitize Myc-overexpressing lymphoma cells partly by inducing HDAC-silenced genes, and suggest synergistic and therapeutic combinations by targeting the genetic link between BETi and HDACi.T he bromodomain and extraterminal (BET) domain family of proteins Brd2, Brd3, Brd4, and BrdT bind via their tandem bromodomains (BD1 and BD2) to acetylated lysines in histones and other proteins (1). On binding, they regulate the transcription of genes critical for cell-cycle progression and apoptosis. Therefore, BET proteins have emerged as interesting proteins for targeted intervention of cancer.Recently, the small-molecule BET inhibitor (+)-JQ-1 (hereafter JQ1) was found to be a potent and specific suppressor of B cell-lineage malignancies (2, 3). In acute myelogenous leukemia, BRD4 is essential for tumor maintenance, and JQ1 recapitulates the effects of RNA interference of BRD4 (4, 5). JQ1 was subsequently shown to have an antiproliferative effect in other hematological malignancies and solid organ tumors including glioblastoma, prostate cancer, and neuroblastoma (6-10). The current model of how BET inhibitors (BETi) inhibit tumor cell proliferation places inhibition of MYC as mediating activity in lymphoid tumors, with Myc-independent activity in some solid tumor types such as lung adenocarcinoma (11). However, it has not been clear in hematopoietic tumor types whether the antiproliferative effects of BETi are mediated by suppression of MYC expression or whether effects on MYC are a correlative bystander of the mechanism, perhaps useful as a biomarker but not necessarily mechanistic (12).We have assessed the effect of RVX2135, a novel and orally bioavailable selective inhibitor of Brd2, Brd3, Brd4, and BrdT, in in vitro and in vivo models of Myc-induced lymphoma. We find that the effects are mediated by broad transcriptional changes and that these are genetically and functionally linked to histone deacetylase inhibitors. Results RVX2135 Blocks Proliferation of Myc-Induced Mouse Lymphoma Cellsand Induces Caspase-Dependent Apoptosis. RVX2135 is a novel small-molecule BET bromodoma...

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“…For instance, Myc, the c-Myc oncogenic TF, is known to directly upregulate a pro-tumorigenic group of miRNAs known as the miR-17-92 cluster, however, the predominant consequence of Myc activation is widespread repression of miRNA expression (38). The involved miRNAs, including miR-26a, miR-150 and miR-195/miR-497, whose tumor-suppressing properties are to be confirmed (39)(40)(41) (42) reported that the loop consisting of c-Myc, miR-17-5p and miR-20a cluster and E2F1 modulates cellular proliferation in P493-6 cells. c-Myc simultaneously activates E2F1 transcription and limits its translation by upregulating miR-17-5p and miR-20a, allowing a tightly controlled proliferative signal.…”

Section: Reported Tf-mirna-target Gene Ffls In Cancermentioning

confidence: 99%

Disruption of the MYC-miRNA-EZH2 loop to suppress aggressive B-cell lymphoma survival and clonogenicity

Cited by 102 publications

References 37 publications

Understanding MYC-driven aggressive B-cell lymphomas: pathogenesis and classification

Understanding MYC-driven aggressive B-cell lymphomas: pathogenesis and classification

BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma

Emerging role of transcription factor-microRNA-target gene feed-forward loops in cancer

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