Germline DDX41 mutations cause ineffective hematopoiesis and myelodysplasia.
BM failure
DDX41
myelodysplastic syndrome
protein synthesis
ribosome biogenesis
snoRNA
Journal
Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472
Informations de publication
Date de publication:
04 11 2021
04 11 2021
Historique:
received:
23
04
2020
revised:
10
05
2021
accepted:
09
08
2021
pubmed:
3
9
2021
medline:
16
11
2021
entrez:
2
9
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34473945
pii: S1934-5909(21)00341-6
doi: 10.1016/j.stem.2021.08.004
pmc: PMC8571055
mid: NIHMS1734503
pii:
doi:
Substances chimiques
DDX41 protein, mouse
EC 3.6.4.13
DEAD-box RNA Helicases
EC 3.6.4.13
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1966-1981.e6Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK102759
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL132071
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK113639
Pays : United States
Organisme : NIDDK NIH HHS
ID : K01 DK121733
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL135795
Pays : United States
Organisme : NHLBI NIH HHS
ID : F31 HL131140
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL135787
Pays : United States
Organisme : NHLBI NIH HHS
ID : F32 HL143993
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests D.T.S. serves on the scientific advisory board at Kurome Therapeutics.
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