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Srsf2P95H/+ mutation exacerbates Asxl1Y588XTg-induced leukemogenesis

ABSTRACT: Srsf2P95H/+ mutation exacerbates Asxl1Y588XTg-induced leukemogenesis

PROVIDER: PRJNA1002285 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25523933_1.fastq.gz	Fastqsanger.gz
	SRR25523933_2.fastq.gz	Fastqsanger.gz
	SRR25523934_1.fastq.gz	Fastqsanger.gz
	SRR25523934_2.fastq.gz	Fastqsanger.gz
	SRR25523935_1.fastq.gz	Fastqsanger.gz

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Srsf2P95H/+ mutation exacerbates Asxl1Y588XTg-induced leukemogenesis

Project description:Additional sex comb-like 1 (ASXL1) is frequently mutated in a spectrum of myeloid malignancies and is associated with poor prognosis. Cancer genome sequencing found that AXL1 mutations frequently co-occur with splicing factors’ mutations (SRSF2, U2AF1, ZRZR2 and SF3B1) in myeloid malignancies. Several studies have reported that Patients with both ASXL1 and splicing mutations have a significantly worse prognosis than those with a single type of mutation, but the mechanisms largely remain to be elucidated. Here we constructed an ASXL1 and SRSF2 co-mutated mouse model and found that Srsf2P95H/+ mutation exacerbated Asxl1Y588XTg-induced leukemogenesis. Mechanistically, the co-existence of ASXL1 mutation and SRSF2 mutation altered the function of hematopoietic stem and progenitor cells and resulted in skewed myeloid differentiation.

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Project description:The role of somatic mitochondrial DNA (mtDNA) mutations in leukemogenesis remains poorly characterized. To determine the impact of somatic mtDNA mutations on the process, we assessed the leukemogenic potential of hematopoietic progenitor cells (HPCs) from mtDNA mutator mice (Polg D257A) with or without NMyc overexpression. We observed a higher incidence of spontaneous leukemogenesis in recipients transplanted with heterozygous Polg HPCs and a lower incidence of NMyc-driven leukemia in those with homozygous Polg HPCs compared to controls. Although mtDNA mutations in heterozygous and homozygous HPCs caused similar baseline impairments in mitochondrial function, only heterozygous HPCs responded to and supported altered metabolic demands associated with NMyc overexpression. Homozygous HPCs showed altered glucose utilization with pyruvate dehydrogenase inhibition due to increased phosphorylation, exacerbated by NMyc overexpression. The impaired growth of NMyc-expressing homozygous HPCs was partially rescued by inhibiting pyruvate dehydrogenase kinase, highlighting a relationship between mtDNA mutation burden and metabolic plasticity in leukemogenesis.

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Increased DNA Methylation of Dnmt3b-Targets Impairs Leukemogenesis (RRBS)

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