Abstract
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.
Highlights
Leukemia is a hematological malignancy characterized by neoplastic clones that are unable to differentiate[1]
acute myeloid leukemia (AML) samples exhibited increased BRD9 expression compared with progenitors and differentiated cells, whereas no difference was observed between AML samples belonging to different cell subgroup based on World Health Organization leukemic classification (Fig. 1a, Supplementary Fig. 1a)
To corroborate BRD9 overexpression in AML, we examined BRD9 expression levels in five ex vivo primary human AML blasts compared with CD34+
Summary
Leukemia is a hematological malignancy characterized by neoplastic clones that are unable to differentiate[1]. Recurring protein-coding mutations and chromosomal aberrations are essential to leukemic pathogenesis, epigenetic mutations critically contribute to its development and/or maintenance[2]. DNA methylation and histone posttranslational modification machinery together with proteins specialized for the interpretation of histone modification (readers) all contribute to leukemogenesis. BRDs are principally involved in gene transcription regulation, cell cycle control, cell growth, DNA damage response, inflammation, and development[4,5]. Overexpression of the histone readers ATAD2 and TRIM24 was associated with poor overall survival in breast cancer[7], whereas BRDT protein was frequently found overexpressed in non-small cell lung cancer and other low survival cancers[8]. Two different short hairpin RNA (shRNA) screening-based studies identified BRD4 and SMARCA4 as targets for acute myeloid leukemia (AML) development and maintenance, Official journal of the Cell Death Differentiation Association
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