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Omics score: 0

SETDB2 links E2A-PBX1 to cell cycle dysregulation in acute leukemia through CDKN2C repression

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

OTHER RELATED OMICS DATASETS IN: PRJNA399516

ORGANISM(S): Homo sapiens

PROVIDER: GSE125334 | GEO | 2019/01/19

REPOSITORIES: GEO

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SETDB2 Links E2A-PBX1 to Cell-Cycle Dysregulation in Acute Leukemia through CDKN2C Repression.

Project description: Not available

| S-EPMC5963704 | biostudies-literature

SETDB2 links E2A-PBX1 to cell cycle dysregulation in acute leukemia through CDKN2C repression [sequencing]

Project description:Acute lymphoblastic leukemia (ALL) is associated with significant morbidity and mortality necessitating further improvements in diagnosis and therapy. Targeted therapies directed against epigenetic regulators, which are frequently mutated or misregulated in acute leukemia, are emerging as candidate approaches in preclinical studies and early trials. However, the epigenetic factors involved in most ALLs are not well defined or functionally characterized. In this study, we demonstrate an oncogenic role for the protein lysine methyltransferase SETDB2 in leukemia pathogenesis. It is over-expressed in a wide spectrum of leukemias, required for their maintenance in vitro and in vivo, and its elevated expression correlates with a poor prognosis in clinical cohorts. In a subset of ALL with the preBCR+ phenotype, SETDB2 expression is maintained as a direct target gene of the chimeric transcription factor E2A-PBX1. In this subset, SETDB2 epigenetically suppresses expression of the cell cycle inhibitor CDKN2C through histone H3K9 tri-methylation thus establishing a novel oncogenic pathway subordinate to E2A-PBX1 that silences a major tumor suppressor in ALL. In contrast, SETDB2 was relatively dispensable for normal hematopoietic stem and progenitor cell proliferation. In addition to targeting SETDB2 alone, its knockdown significantly enhanced sensitivity to kinase and epigenetic inhibitors suggesting a potential approach to future combination treatments. Our studies define an epigenetic role for SETDB2 in leukemia pathogenesis, and provide a mechanistic rationale for targeting SETDB2 therapeutically in a subset of leukemia.

2018-05-30 | GSE102947 | GEO