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Ferrata Storti Foundation
Haematologica 2022 Volume 107(3):644-654
Ddx41 inhibition of DNA damage signaling permits erythroid progenitor expansion in zebrafish
Joshua T. Weinreb,1,2 Varun Gupta,3 Elianna Sharvit,1 Rachel Weil,1 and Teresa V. Bowman1,2,4
1Albert Einstein College of Medicine, Department of Developmental and Molecular Biology; 2Albert Einstein College of Medicine, Gottesman Institute for Stem Cell Biology and Regenerative Medicine; 3Albert Einstein College of Medicine, Department of Cell Biology and 4Albert Einstein College of Medicine and Montefiore Medical Center, Department of Medicine (Oncology), Bronx, NY, USA
ABSTRACT
DEAD-box Helicase 41 (DDX41) is a recently identified factor mutated in hematologic malignancies whose function in hematopoiesis is unknown. Using an in vivo model of Ddx41 defi- ciency, we unveiled a critical role for this helicase in regulating erythro- poiesis. We demonstrated that loss of ddx41 leads to anemia caused by diminished proliferation and defective differentiation of erythroid pro- genitors. Mis-expression and alternative splicing of cell cycle genes is rampant in ddx41 mutant erythroid progenitors. We delineated that the DNA damage response is activated in mutant cells resulting in an Ataxia- telangiectasia mutated (ATM) and Ataxia-telangiectasia and Rad3-related (ATR)-triggered cell cycle arrest. Inhibition of these kinases partially sup- pressed ddx41 mutant anemia. These findings establish a critical function for Ddx41 in promoting healthy erythropoiesis via protection from genomic stress and delineate a mechanistic framework to explore a role for ATM and ATR signaling in DDX41-mutant hematopoietic patholo- gies.
Introduction
Mutations in DEAD-box Helicase 41 (DDX41) were identified recently in hemato- logic malignancies including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and acute erythroid leukemia (AEL).1,2 Germline DDX41 frameshift mutations are loss-of-function and somatic missense mutations are thought to result in hypomorphic helicase activity.1,3 The human genetics thus suggest that diminished function of this helicase is detrimental to hematopoiesis, but this has yet to be demonstrated in an animal model.
In particular, a significant number of DDX41-mutated MDS patients experience mild cytopenia in the years preceding diagnosis, indicating that anemia may be one of the first warning signs of disease.4 Anemia in MDS is attributed to numerous cel- lular mechanisms including erythroid precursor apoptosis, defective progenitor expansion, and ineffective erythrocytic maturation.5-7 The clinical findings suggest DDX41 could be important in erythropoiesis, but the cellular and molecular under- pinnings remain unclear. Roles for DDX41 have been implicated in genomic stability, inflammation, and splicing, all processes linked to hematopoietic health, but the cur- rent lack of DDX41 mutant animal models has slowed exploration of its function in the blood system.8-11
In order to uncover the in vivo role of DDX41 in erythropoiesis, we established a zebrafish ddx41 loss-of-function mutant. We demonstrated that ddx41 mutants develop anemia due to a decrease in erythroid progenitor expansion and defective differentiation. Mechanistically, the erythroid proliferative defect is due in part to ATM- and ATR-mediated cell cycle arrest induced by elevated DNA damage as well as mis-expression and alternative splicing of cell cycle regulators. Our data demon- strate that Ddx41 plays a critical role in hematopoiesis and provide a possible mech- anism by which anemia may arise in DDX41-mutated hematopoietic pathologies.
Hematopoiesis
Correspondence:
TERESA V. BOWMAN
teresa.bowman@einsteinmed.org
Received: April 28, 2020. Accepted: March 16, 2021. Pre-published: March 25, 2021.
https://doi.org/10.3324/haematol.2020.257246 ©2022 Ferrata Storti Foundation
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