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

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

PROVIDER: PRJNA1037498 | ENA |

REPOSITORIES: ENA

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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 [CD71]

2024-06-13 | GSE247403 | 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]

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 [LSK]

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

| PRJNA1037501 | 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

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

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

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

Discriminating activities of DEAD-Box Helicase 41 from myeloid malignancy-associated germline variants by genetic rescue

Project description:Although DEAD-box helicase 41 (DDX41) is implicated in oncogenic and innate immune mechanisms, there are many unanswered questions about how the ever-increasing spectrum of genetic variants impacts DDX41 activity. Here, we describe a facile genetic rescue assay that discriminates activities of DDX41 from those of human myeloid malignancy-linked germline and somatic DDX41 mutants. Our analyses revealed that the variants were impaired in their intrinsic RNA-regulatory activities and to induce monocytic differentiation markers. It will be instructive to extend these analyses to more broadly conduct structure/function assessments for clinical genetic curation and leverage the quantitative assay to elucidate mechanisms and interventions that promote and/or oppose DDX41 function, thereby influencing DDX41-linked pathogenicity.

2022-12-04 | GSE208400 | GEO

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