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CEBPA Dysfunction Intiates CSF3R Mutant Acute Myeloid Leukemia Through Disruption of Myeloid Lineage Enhancers (ChIP-seq)

ABSTRACT: Acute Myeloid Leukemia (AML) develops due to the acquisition of mutations from multiple functional classes. Here, we demonstrate that activating mutations in the granulocyte colony stimulating factor receptor (CSF3R), cooperate with loss of function mutations in the transcription factor CEBPA to promote acute leukemia development. Terminal myeloid differentiation in response to granulocyte colony-stimulating factor signaling requires wild type CEBPA and is blocked by mutations in CEBPA. Inhibition of the histone demethylase LSD1, restores differentiation and in combination with JAK/STAT blockade, produces significant disease response in vivo. Mutant CEBPA blocks myeloid differentiation by preventing the activation of differentiation-associated enhancers. As enhancer activation precedes promoter activation, CEBPA mutations must occur prior to CSF3R mutations to effectively block differentiation and promote leukemia formation in vivo. This study demonstrates that order-dependent oncogene interaction is a fundamental process in AML. Dissecting this process is critical for understanding disease evolution to enable the development of effective therapeutics.

ORGANISM(S): Mus musculus

PROVIDER: GSE122162 | GEO | 2019/12/02

REPOSITORIES: GEO

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CEBPA Dysfunction Intiates CSF3R Mutant Acute Myeloid Leukemia Through Disruption of Myeloid Lineage Enhancers (Microarray)

Project description:Acute Myeloid Leukemia (AML) develops due to the acquisition of mutations from multiple functional classes. Here, we demonstrate that activating mutations in the granulocyte colony stimulating factor receptor (CSF3R), cooperate with loss of function mutations in the transcription factor CEBPA to promote acute leukemia development. Terminal myeloid differentiation in response to granulocyte colony-stimulating factor signaling requires wild type CEBPA and is blocked by mutations in CEBPA. Inhibition of the histone demethylase LSD1, restores differentiation and in combination with JAK/STAT blockade, produces significant disease response in vivo. Mutant CEBPA blocks myeloid differentiation by preventing the activation of differentiation-associated enhancers. As enhancer activation precedes promoter activation, CEBPA mutations must occur prior to CSF3R mutations to effectively block differentiation and promote leukemia formation in vivo. This study demonstrates that order-dependent oncogene interaction is a fundamental process in AML. Dissecting this process is critical for understanding disease evolution to enable the development of effective therapeutics.

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CEBPA Dysfunction Intiates CSF3R Mutant Acute Myeloid Leukemia Through Disruption of Myeloid Lineage Enhancers

Project description:CEBPA Dysfunction Intiates CSF3R Mutant Acute Myeloid Leukemia Through Disruption of Myeloid Lineage Enhancers

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