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Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

OTHER RELATED OMICS DATASETS IN: PRJNA315686PRJNA315685PRJNA315563

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE79391 | GEO | 2016/05/01

SECONDARY ACCESSION(S): PRJNA315685

REPOSITORIES: GEO

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Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition.

Project description:Here we show that acute myeloid leukemia (AML) cells require the BRD9 subunit of the SWI-SNF chromatin-remodeling complex to sustain MYC transcription, rapid cell proliferation and a block in differentiation. Based on these observations, we derived small-molecule inhibitors of the BRD9 bromodomain that selectively suppress the proliferation of mouse and human AML cell lines. To establish these effects as on-target, we engineered a bromodomain-swap allele of BRD9 that retains functionality despite a radically altered bromodomain pocket. Expression of this allele in AML cells confers resistance to the antiproliferative effects of our compound series, thus establishing BRD9 as the relevant cellular target. Furthermore, we used an analogous domain-swap strategy to generate an inhibitor-resistant allele of EZH2. To our knowledge, our study provides the first evidence for a role of BRD9 in cancer and reveals a simple genetic strategy for constructing resistance alleles to demonstrate on-target activity of chemical probes in cells.

| S-EPMC4990482 | biostudies-literature

Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition (ChIP-seq)

Project description:Our study shows that acute myeloid leukemia (AML) cells require the BRD9 subunit of the SWI/SNF chromatin remodeling complex to sustain MYC transcription, rapid cell proliferation, and a block in differentiation. Based on these observations, we derived small-molecule inhibitors of the BRD9 bromodomain, which selectively suppressed the proliferation of mouse and human AML cell lines. To establish these effects as on-target, we engineered a bromodomain-swap allele of BRD9, which retains functionality despite a radically altered bromodomain pocket. Expression of this allele in AML cells conferred resistance to the anti-proliferative effects of our compound series, thus establishing BRD9 as the relevant cellular target. Furthermore, we used an analogous domain-swap strategy to generate an inhibitor-resistant allele of EZH2. Our study provides the first evidence for a role of BRD9 in cancer and reveals a simple genetic strategy for constructing resistance alleles to demonstrate on-target activity of chemical probes in cells.

2016-05-01 | GSE79360 | GEO

Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition (RNA-seq)

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Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition

Project description:Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition

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Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition (ChIP-seq)

Project description:Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition (ChIP-seq)

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Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition (RNA-seq)

Project description:Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition (RNA-seq)

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BET inhibition releases the Mediator complex from specific cis elements in acute myeloid leukemia cells

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