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Germline DDX41 mutations cause ineffective hematopoiesis and myelodysplasia

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2021

Cell Stem Cell. 2021 Aug 27;S1934-5909(21)00341-6. doi: 10.1016/j.stem.2021.08.004. Online ahead of print.

Germline DDX41 mutations cause ineffective hematopoiesis and myelodysplasia

Timothy M Chlon, Emily Stepanchick, Courtney E Hershberger, Noah J Daniels, Kathleen M Hueneman, Ashley Kuenzi Davis, Kwangmin Choi, Yi Zheng, Carmelo Gurnari, Torsten Haferlach, Richard A Padgett, Jaroslaw P Maciejewski, Daniel T Starczynowski

Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA. Translational Hematology and Oncology Research Department, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44106, USA. Department of Biomedicine and Prevention & PhD in Immunology, Molecular Medicine and Applied Biotechnology, University of Rome, Tor Vergata, Rome, Italy. Munich Leukemia Laboratory, Munich, Germany.

Service type: Knock-in mice

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. Keywords: BM failure; DDX41; myelodysplastic syndrome; protein synthesis; ribosome biogenesis; snoRNA.

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