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DDX41 heterozygosity impairs hematopoietic progenitor cell fitness and cooperates with p53 mutation to drive malignancy [LSK]

ABSTRACT: DDX41 heterozygosity impairs hematopoietic progenitor cell fitness and cooperates with p53 mutation to drive malignancy [LSK]

PROVIDER: PRJNA1037501 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26779900_1.fastq.gz	Fastqsanger.gz
	SRR26779900_2.fastq.gz	Fastqsanger.gz
	SRR26779901_1.fastq.gz	Fastqsanger.gz
	SRR26779901_2.fastq.gz	Fastqsanger.gz
	SRR26779895_1.fastq.gz	Fastqsanger.gz

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DDX41 heterozygosity impairs hematopoietic progenitor cell fitness and cooperates with p53 mutation to drive malignancy [LSK]

Project description:Germline heterozygous mutations in DDX41 predispose individuals to hematologic malignancies in adulthood. Most of these DDX41 mutations result in a truncated protein, leading to loss of protein function. To investigate the impact of these mutations on hematopoiesis, we generated mice with hematopoietic-specific knockout of one Ddx41 allele. Under normal steady-state conditions, there was minimal effect on lifelong hematopoiesis, resulting in a mild yet persistent reduction in red blood cell counts. However, stress induced by transplantation of the Ddx41+/- BM resulted in hematopoietic stem/progenitor cell (HSPC) defects and onset of hematopoietic failure upon aging. Transcriptomic analysis of HSPC subsets from the transplanted BM revealed activation of cellular stress responses, including upregulation of p53 target genes in erythroid progenitors. To understand how the loss of p53 affects the phenotype of Ddx41+/- HSPCs, we generated mice with combined Ddx41 and Trp53 heterozygous deletions. The reduction in p53 expression rescued the fitness defects in HSPC caused by Ddx41 heterozygosity. However, the combined Ddx41 and Trp53 mutant mice were prone to developing hematologic malignancies that resemble human myelodysplastic syndrome and acute myeloid leukemia. In conclusion, DDX41 heterozygosity causes dysregulation of the response to hematopoietic stress, which increases the risk of transformation with a p53 mutation.

2024-06-13 | GSE247404 | GEO

DDX41 heterozygosity impairs hematopoietic progenitor cell fitness and cooperates with p53 mutation to drive malignancy [MOLM13]

2024-06-13 | GSE247408 | GEO

DDX41 heterozygosity impairs hematopoietic progenitor cell fitness and cooperates with p53 mutation to drive malignancy [CD71]

2024-06-13 | GSE247403 | GEO

DDX41 heterozygosity impairs hematopoietic progenitor cell fitness and cooperates with p53 mutation to drive malignancy

Project description:DDX41 heterozygosity impairs hematopoietic progenitor cell fitness and cooperates with p53 mutation to drive malignancy

| PRJNA1037498 | ENA

DDX41 heterozygosity impairs hematopoietic progenitor cell fitness and cooperates with p53 mutation to drive malignancy [CD71]

Project description:DDX41 heterozygosity impairs hematopoietic progenitor cell fitness and cooperates with p53 mutation to drive malignancy [CD71]

| PRJNA1037495 | ENA

DDX41 heterozygosity impairs hematopoietic progenitor cell fitness and cooperates with p53 mutation to drive malignancy [MOLM13]

Project description:DDX41 heterozygosity impairs hematopoietic progenitor cell fitness and cooperates with p53 mutation to drive malignancy [MOLM13]

| PRJNA1037504 | ENA

Single cell gene expression analysis of hematopoietic progenitors in Ddx41-heterozygous mice

Project description:To determine the effect of heterozygosity of Ddx41 on hematopoiesis, we conducted single cell transcriptome analysis on hematopoietic progenitor cells from Ddx41-heterozygous and control bone marrow. We found that heterozygoisty of Ddx41 did not signficantly alter the distribution of progenitor cell types, and changes in gene expression within the clusters were minimal.

2024-06-13 | GSE248396 | GEO

Total RNA sequencing of mouse LSK cells in E14.5 fetal liver

Project description:The study is to obtain a transcriptome-wide map of prenatal murine stem and progenitor cells. VavCre+ mice were used for conditional knockout of Ddx41. Wild-type, Ddx41 heterozygous (Ddx41+/-) and Ddx41 knockout (Ddx41-/-) LSK cells from embryonic 14.5 day fetal liver were harvested (three samples from each group) for RNA. Gene expression analysis and alternative splicing analysis were performed. RNA-seq data were confirmed by RT-qPCR and regular PCR followed by gel quantification. A global change of gene expression and substantial differential splicing events were observed in KO samples compared to WT and het.

2022-02-04 | GSE178979 | GEO

Inherited and somatic defects in DDX41 in myeloid neoplasms

Project description:Most cases of adult myeloid neoplasms are routinely assumed to be sporadic. Here, we describe an adult familial acute myeloid leukemia (AML) syndrome caused by germline mutations in the DEAD/H-Box helicase gene DDX41. DDX41 was also found to be affected by somatic mutations in sporadic cases of myeloid neoplasms as well as in a biallelic fashion in 50% of patients with germline DDX41 mutations. Moreover, corresponding deletions on 5q35.3 present in 6% of cases lead to haploinsufficient DDX41 expression. DDX41 lesions caused altered pre-mRNA splicing and RNA processing. DDX41 is exemplary of other RNA helicase genes also affected by somatic mutations, suggesting that they constitute a family of tumor suppressor genes. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from cryopreserved diagnostic bone marrow or peripheral blood samples.

2015-04-01 | E-GEOD-66668 | biostudies-arrayexpress

DDX41 heterozygosity impairs hematopoietic progenitor cell fitness and cooperates with p53 mutation to drive malignancy

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-06-13 | GSE247409 | GEO