BRD9 binds cell type-specific chromatin regions regulating leukemic cell survival via STAT5 inhibition

Nunzio Del Gaudio, Antonella Di Costanzo, Ning Qing Liu, Lidio Conte, Antimo Migliaccio, Michiel Vermeulen, Joost H.A. Martens, Hendrik G. Stunnenberg, Angela Nebbioso, Lucia Altucci

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

22 Citaten (Scopus)

Samenvatting

Leukemia is characterized by genetic and epigenetic mutations resulting in selection of cancer cells, which are unable to differentiate. Although genetic alterations are difficult to target, the epigenome is intrinsically dynamic and readily offers new therapeutic strategies. Thus, identifying cancer-specific context-dependent targets and unraveling their biological function may open up new therapeutic perspectives. Here we identify bromodomain-containing protein 9 (BRD9) as a critical target required in acute myeloid leukemia (AML). We show that BRD9 is overexpressed in AML cells including ex vivo primary blasts compared with CD34 + cells. By targeting BRD9 expression in AML, we observed an alteration in proliferation and survival, ultimately resulting in the induction of apoptosis. Intriguingly, genome-wide profiling revealed that BRD9 binds enhancer regions in a cell type-specific manner, regulating cell type-related processes. We unveil a novel BRD9-sustained STAT5 pathway activation via regulation of SOCS3 expression levels. Our findings identify a previously undescribed BRD9-STAT5 axis as critical for leukemia maintenance, suggesting BRD9 as a potential therapeutic target.

Originele taal-2Engels
Artikelnummer338
TijdschriftCell Death and Disease
Volume10
Nummer van het tijdschrift5
DOI's
StatusGepubliceerd - 1 mei 2019
Extern gepubliceerdJa

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