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Targeting of DNMT3A hotspot mutations in Clonal Hematopoiesis and Acute Myeloid Leukemia

ABSTRACT: Targeting of DNMT3A hotspot mutations in Clonal Hematopoiesis and Acute Myeloid Leukemia

PROVIDER: PRJNA612341 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11298882_1.fastq.gz	Fastqsanger.gz
	SRR11298882_2.fastq.gz	Fastqsanger.gz
	SRR11298883_1.fastq.gz	Fastqsanger.gz
	SRR11298883_2.fastq.gz	Fastqsanger.gz
	SRR11298884_1.fastq.gz	Fastqsanger.gz

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Targeting of DNMT3A hotspot mutations in Clonal Hematopoiesis and Acute Myeloid Leukemia

Project description:Somatic mutations in DNA Methyltransferase 3A (DNMT3A) with a hotspot in exon 23 at Arginine 882 (DNMT3AR882mut) are the most frequent single mutations in clonal hematopoiesis. Here we analyze the expression of genes and endogenous retrovirus (ERV) sequences in a murine model carrying human DNMT3A-R882H mutation in one allele of the endogenous DNMT3A with respect to normal condition and azacitidine treatment.

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DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts

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Project description:Clonal hematopoiesis (CH) reflects clonal expansion of blood stem and progenitor cells with somatic mutations. We leveraged multi-modality single-cell sequencing to capture mutation status together with the transcriptome and methylome of CD34+ hematopoietic progenitor cells from five individuals with DNMT3A R882-mutated CH.

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Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations

Project description:DNA methyltransferases DNMT3A- and DNMT3B-mediated de novo DNA methylation critically regulates epigenomic and transcriptomic patterning during development. The hotspot DNMT3A mutations at the site of Arg822 (R882) promote macro-oligomer formation, leading to aberrant DNA methylation that in turn contributes to pathogenesis of acute myeloid leukemia (AML). However, the molecular basis underlying the hotspot mutation-induced functional mis-regulation of DNMT3A remains unclear. Here, we report the crystal structure of DNMT3A methyltransferase (MTase) domain, revealing a molecular basis for its DNMT3B-distinct oligomerization behavior. Introducing DNMT3B-converting mutations to DNMT3A R882 mutants also led to structure determination of R882H- and R882C-mutated DNMT3A, which show enhanced intermolecular contacts than wild-type DNMT3A. Consistently, our in vitro and genomic DNA methylation analyses reveal that the DNMT3B-converting mutations eliminate the gain-of-function effect of the DNMT3A R882 mutations in cells. Together, this study provides mechanistic insights into DNMT3A R882 mutation-triggered aberrant oligomerization and DNA hypomethylation in AML, with important implications in cancer therapy.

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