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.

Chlon, T.m., Stepanchick, E., Hershberger, C.e., Daniels, N.j., Hueneman, K.m., Kuenzi Davis, A., et al. (2021). Germline DDX41 mutations cause ineffective hematopoiesis and myelodysplasia. CELL STEM CELL, 28(11), 1966-1981 [10.1016/j.stem.2021.08.004].

Germline DDX41 mutations cause ineffective hematopoiesis and myelodysplasia

Gurnari, Carmelo
Validation
;
2021-11-04

Abstract

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.
4-nov-2021
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/15 - MALATTIE DEL SANGUE
English
BM failure; DDX41; myelodysplastic syndrome; protein synthesis; ribosome biogenesis; snoRNA
Chlon, T.m., Stepanchick, E., Hershberger, C.e., Daniels, N.j., Hueneman, K.m., Kuenzi Davis, A., et al. (2021). Germline DDX41 mutations cause ineffective hematopoiesis and myelodysplasia. CELL STEM CELL, 28(11), 1966-1981 [10.1016/j.stem.2021.08.004].
Chlon, Tm; Stepanchick, E; Hershberger, Ce; Daniels, Nj; Hueneman, Km; Kuenzi Davis, A; Choi, K; Zheng, Y; Gurnari, C; Haferlach, T; Padgett, Ra; Maci...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/311859
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