Cell Stem Cell
Volume 28, Issue 11, 4 November 2021, Pages 1966-1981.e6
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Article
Germline DDX41 mutations cause ineffective hematopoiesis and myelodysplasia

https://doi.org/10.1016/j.stem.2021.08.004Get rights and content
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Highlights

  • Monoallelic DDX41 mutations result in age-dependent hematopoietic defects

  • DDX41 regulates snoRNA processing and protein synthesis

  • Biallelic DDX41 mutations are not compatible with proliferating hematopoietic cells

  • Biallelic DDX41 mutant cells are disease modifying and accelerate hematopoietic defects

Summary

DDX41 mutations are the most common germline alterations in adult myelodysplastic syndromes (MDSs). The majority of affected individuals harbor germline monoallelic frameshift DDX41 mutations and subsequently acquire somatic mutations in their other DDX41 allele, typically missense R525H. Hematopoietic progenitor cells (HPCs) with biallelic frameshift and R525H mutations undergo cell cycle arrest and apoptosis, causing bone marrow failure in mice. Mechanistically, DDX41 is essential for small nucleolar RNA (snoRNA) processing, ribosome assembly, and protein synthesis. Although monoallelic DDX41 mutations do not affect hematopoiesis in young mice, a subset of aged mice develops features of MDS. Biallelic mutations in DDX41 are observed at a low frequency in non-dominant hematopoietic stem cell clones in bone marrow (BM) from individuals with MDS. Mice chimeric for monoallelic DDX41 mutant BM cells and a minor population of biallelic mutant BM cells develop hematopoietic defects at a younger age, suggesting that biallelic DDX41 mutant cells are disease modifying in the context of monoallelic DDX41 mutant BM.

Keywords

myelodysplastic syndrome
DDX41
protein synthesis
snoRNA
ribosome biogenesis
BM failure

Data and code availability

Next Generation Sequencing data, including data for mouse RNA-Seq, HyperTRIBE, and CRISPR knockout screen, have been deposited at GEO and are publicly available as of the date of publication. Accession numbers are listed in the key resources table. Patient sequencing data is available by request to Torsten Haferlach, Munich Leukemia Laboratory, Munich, Germany ([email protected]). Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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