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A CHAF1B-dependent molecular switch in hematopoiesis and leukemia pathogenesis

ABSTRACT: A CHAF1B-dependent molecular switch in hematopoiesis and leukemia pathogenesis

PROVIDER: PRJNA491485 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7865900.fastq.gz	Fastqsanger.gz
	SRR7865910_1.fastq.gz	Fastqsanger.gz
	SRR7865910_2.fastq.gz	Fastqsanger.gz
	SRR7865920.fastq.gz	Fastqsanger.gz
	SRR7865930.fastq.gz	Fastqsanger.gz

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A CHAF1B-dependent molecular switch in hematopoiesis and leukemia pathogenesis

Project description:CHAF1B is the p60 subunit of the chromatin assembly factor (CAF1) complex, which is responsible for assembly of H3.1/H4 heterodimers at the replication fork during S phase. Here we report that CHAF1B is required for normal hematopoiesis while its overexpression promotes leukemia. CHAF1B has a pro-leukemia effect by binding chromatin at discrete sites and interfering with occupancy of transcription factors that promote myeloid differentiation, such as CEBPA. Reducing Chaf1b activity by either heterozygous deletion or overexpression of a CAF1 dominant negative allele was sufficient to suppress leukemogenesis in vivo without impairing normal hematopoiesis.

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Project description:Acute myeloid leukemia (AML) is an aggressive blood cancer that stems from the rapid expansion of immature leukemic blasts in the bone marrow. Mutations in epigenetic factors represent the largest category of genetic drivers of AML. The chromatin assembly factor CHAF1B is a master epigenetic regulator of transcription associated with self-renewal and the undifferentiated state of AML blasts. Upregulation of CHAF1B, as observed in almost all AML samples, promotes leukemic progression by repressing transcription of differentiation factors and tumor suppressors. However, the specific factors regulated by CHAF1B and their contributions to leukemogenesis are unstudied. We analyzed RNAseq from mouse MLL-AF9 leukemic cells and bone marrow aspirates representing a diverse collection of pediatric AML samples and identified the E3 ubiquitin ligase TRIM13 as a target of CHAF1B-mediated transcriptional repression associated with leukemogenesis. We found that CHAF1B binds the promoter of TRIM13, resulting in its transcriptional repression. In turn, TRIM13 suppresses self-renewal of leukemic cells by promoting pernicious entry into the cell cycle through its nuclear localization and catalytic ubiquitination of cell cycle-promoting protein CCNA1. Overexpression of TRIM13 initially prompts a proliferative burst in AML cells that is followed by exhaustion, while loss of total TRIM13 or deletion of its catalytic domain enhanced leukemogenesis in AML cell lines and patient-derived xenografts. These data suggest that CHAF1B promotes leukemic development in part by repressing TRIM13 expression, and that this relationship is necessary for leukemic progression.

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