Fusion of ZMYND8 and RELA Genes in Acute Erythroid Leukemia

Panagopoulos, Ioannis; Micci, Francesca; Thorsen, Jim; Haugom, Lisbeth; Buechner, Jochen; Kerndrup, Gitte; Tierens, Anne; Zeller, Bernward; Heim, Sverre

doi:10.1371/journal.pone.0063663

Cited by 40 publications

(39 citation statements)

References 19 publications

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“…Moreover, withanolide F modulates the expression of several genes involved in chromatin function and remodeling. While it remains to be determined which of these genes are critical, they include the bromodomain factor ZMYND8 involved in DNA repair [37] and implicated in cancer as a fusion protein [38]; the key Polycomb repressive complex 2 (PRC2) component EED, which associates with EZH2 (which trimethylates H3K27 causing gene silencing) and also functions in the coordination of PRC complexes [39]; the SWI/SNF chromatin remodeling factor SMARCAL1 involved in genome integrity (e.g., [40]); and multiple HISTONE genes.…”

Section: Discussionmentioning

confidence: 99%

Long-Lasting WNT-TCF Response Blocking and Epigenetic Modifying Activities of Withanolide F in Human Cancer Cells

et al. 2016

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The WNT-TCF signaling pathway participates in adult tissue homeostasis and repair, and is hyperactive in a number of human diseases including cancers of the colon. Whereas to date there are no antagonists approved for patient use, a potential problem for their sustained use is the blockade of WNT signaling in healthy tissues, thus provoking potentially serious co-lateral damage. Here we have screened a library of plant and microorganism small molecules for novel WNT signaling antagonists and describe withanolide F as a potent WNT-TCF response blocker. This steroidal lactone inhibits TCF-dependent colon cancer xenograft growth and mimics the effects of genetic blockade of TCF and of ivermectin, a previously reported WNT-TCF blocker. However, withanolide F is unique in that it imposes a long-lasting repression of tumor growth, WNT-TCF targets and cancer stem cell clonogenicity after drug treatment. These findings are paralleled by its modulation of chromatin regulators and its alteration of overall H3K4me1 levels. Our results open up the possibility to permanently repress essential signaling responses in cancer cells through limited treatments with small molecules.

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Section: Discussionmentioning

confidence: 99%

Long-Lasting WNT-TCF Response Blocking and Epigenetic Modifying Activities of Withanolide F in Human Cancer Cells

et al. 2016

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“…ZMYND8 has been implicated in cancer as a cutaneous T-cell lymphoma-associated antigen, as a fusion protein with the oncogene RELA in acute erythroid leukemia and with CEP250 in breast cancer (Eichmuller et al 2001;Panagopoulos et al 2013;Wada et al 2014). Both of the ZMYND8 fusions reported remove the MYND domain, the NuRD complex interaction region that we identified in ZMYND8, suggesting that defective CHD4 chromatin recruitment could contribute to these pathologies.…”

Section: Brd Proteins As Mediators Of the Ddrmentioning

confidence: 99%

Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination

et al. 2015

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How chromatin shapes pathways that promote genome-epigenome integrity in response to DNA damage is an issue of crucial importance. We report that human bromodomain (BRD)-containing proteins, the primary ''readers'' of acetylated chromatin, are vital for the DNA damage response (DDR). We discovered that more than one-third of all human BRD proteins change localization in response to DNA damage. We identified ZMYND8 (zinc finger and MYND [myeloid, Nervy, and DEAF-1] domain containing 8) as a novel DDR factor that recruits the nucleosome remodeling and histone deacetylation (NuRD) complex to damaged chromatin. Our data define a transcription-associated DDR pathway mediated by ZMYND8 and the NuRD complex that targets DNA damage, including when it occurs within transcriptionally active chromatin, to repress transcription and promote repair by homologous recombination. Thus, our data identify human BRD proteins as key chromatin modulators of the DDR and provide novel insights into how DNA damage within actively transcribed regions requires chromatin-binding proteins to orchestrate the appropriate response in concordance with the damage-associated chromatin context.

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“…At a cytogenetic level, most cases of PEL have a complex karyotype, with frequent abnormalities involving chromosomes 5 and 7 . Occasional fusion genes secondary to chromosomal translocations have been described in PEL, such as t(1;16)(p31;q24)/NFIA‐CBFA2T3 and t(11;20)(p11;q11)/ZMYND8‐RELA …”

Section: Geneticsmentioning

confidence: 99%

Pure erythroid leukemia

Wang

Medeiros

et al. 2017

American J Hematol

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The category of acute erythroid leukemia was significantly revised in the recently published 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms. In the previous 2008 WHO classification, acute erythroid leukemia was categorized into two subtypes: erythroleukemia and pure erythroid leukemia (PEL), whereas in the 2016 WHO update, erythroleukemia was merged into myelodysplastic syndrome, and PEL becomes the only type of acute erythroid leukemia. PEL is a rare and aggressive form of acute leukemia whose biology remains poorly characterized. In this review, we discuss the clinicopathologic features, diagnosis, putative pathogenesis, and molecular biology of PEL, with an overview of novel concepts and future directions in this area.wileyonlinelibrary.com/journal/ajh Am J Hematol. 2017;92:292-296

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Fusion of ZMYND8 and RELA Genes in Acute Erythroid Leukemia

Cited by 40 publications

References 19 publications

Long-Lasting WNT-TCF Response Blocking and Epigenetic Modifying Activities of Withanolide F in Human Cancer Cells

Long-Lasting WNT-TCF Response Blocking and Epigenetic Modifying Activities of Withanolide F in Human Cancer Cells

Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination

Pure erythroid leukemia

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