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DOT1L inhibitors block abnormal self-renewal induced by cohesin loss [RNA-seq]

ABSTRACT: Acute myelogenous leukemia (AML) is a high-risk malignancy characterized by a diverse spectrum of somatic genetic alterations. The mechanisms by which these mutations contribute to leukemia development and how this informs the use of targeted therapies is critical to improving outcomes. Importantly, how to target loss-of-function mutations has been a critical challenge in precision medicine. Heterozygous inactivating mutations in cohesin complex genes contribute to AML by increasing the self-renewal capacity of hematopoietic stem and progenitor cells (HSPCs) by altering PRC2 targeting to induce HOXA9 expression, a key self-renewal transcription factor. Here we sought to delineate the mechanism underpinning the enhanced self-renewal conferred by cohesin haploinsufficiency. Using primary (HSPCs) as a model we demonstrate that a reduction in a core cohesin subunit is associated with decreased H3K27me3 and increased H3K79me2, along with increased self-renewal capacity and a leukemic transcriptional profile. Inhibition of DOT1L in cohesin-depleted HSPCs restored normal self-renewal, H3K27me3 and H3K79me2 levels, and gene expression, identifying DOT1L as a potential therapeutic target in cohesin haploinsufficient AML. Together our data further characterizes the mechanism by which cohesin mutations contribute to AML and identifies DOT1L as a potential therapeutic target for AML patients harboring cohesin mutations.

ORGANISM(S): Mus musculus

PROVIDER: GSE140359 | GEO | 2021/02/25

REPOSITORIES: GEO

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DOT1L inhibitors block abnormal self-renewal induced by cohesin loss [ChIP-seq]

Project description:Acute myelogenous leukemia (AML) is a high-risk malignancy characterized by a diverse spectrum of somatic genetic alterations. The mechanisms by which these mutations contribute to leukemia development and how this informs the use of targeted therapies is critical to improving outcomes. Importantly, how to target loss-of-function mutations has been a critical challenge in precision medicine. Heterozygous inactivating mutations in cohesin complex genes contribute to AML by increasing the self-renewal capacity of hematopoietic stem and progenitor cells (HSPCs) by altering PRC2 targeting to induce HOXA9 expression, a key self-renewal transcription factor. Here we sought to delineate the mechanism underpinning the enhanced self-renewal conferred by cohesin haploinsufficiency. Using primary (HSPCs) as a model we demonstrate that a reduction in a core cohesin subunit is associated with decreased H3K27me3 and increased H3K79me2, along with increased self-renewal capacity and a leukemic transcriptional profile. Inhibition of DOT1L in cohesin-depleted HSPCs restored normal self-renewal, H3K27me3 and H3K79me2 levels, and gene expression, identifying DOT1L as a potential therapeutic target in cohesin haploinsufficient AML. Together our data further characterizes the mechanism by which cohesin mutations contribute to AML and identifies DOT1L as a potential therapeutic target for AML patients harboring cohesin mutations.

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DOT1L inhibitors block abnormal self-renewal induced by cohesin loss

Project description:DOT1L inhibitors block abnormal self-renewal induced by cohesin loss

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High ERG expression in human HSPCs promotes progenitor but not stem cell proliferation and molecular signatures that are enriched in high ERG leukemia.

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DOT1L inhibitors block abnormal self-renewal induced by cohesin loss [RNA-seq]

Project description:DOT1L inhibitors block abnormal self-renewal induced by cohesin loss [RNA-seq]

| PRJNA589334 | ENA

DOT1L inhibitors block abnormal self-renewal induced by cohesin loss [ChIP-seq]

Project description:DOT1L inhibitors block abnormal self-renewal induced by cohesin loss [ChIP-seq]

| PRJNA589335 | ENA