title: H2AX deficiency is associated with erythroid dysplasia and compromised haematopoietic stem cell function.
abstract: Myelodysplastic syndromes (MDS) are clonal disorders of haematopoiesis characterised by dysplastic changes of major myeloid cell lines. However, the mechanisms underlying these dysplastic changes are poorly understood. Here, we used a genetically modified mouse model and human patient data to examine the physiological roles of H2AX in haematopoiesis and how the loss of H2AX contributes to dyserythropoiesis in MDS. H2AX knockout mice showed cell-autonomous anaemia and erythroid dysplasia, mimicking dyserythropoiesis in MDS. Also, dyserythropoiesis was increased in MDS patients with the deletion of chromosome 11q23, where H2AX is located. Although loss of H2AX did not affect the early stage of terminal erythropoiesis, enucleation was decreased. H2AX deficiency also led to the loss of quiescence of hematopoietic stem and progenitor cells, which dramatically compromised their bone marrow engraftment. These results reveal important roles of H2AX in late-stage terminal erythropoiesis and hematopoietic stem cell function.
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Baobing
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Tan
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Mei
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Yiting
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Juehua
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Ji
mesh_terms: D000748:Anemia, Macrocytic / Q000235:genetics / Q000473:pathology; D000818:Animals; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D004908:Erythrocyte Inclusions; D041905:Erythroid Cells / Q000378:metabolism* / Q000473:pathology*; D004920:Erythropoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006657:Histones / Q000172:deficiency*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009190:Myelodysplastic Syndromes / Q000175:diagnosis* / Q000235:genetics*; D011379:Prognosis
chemical_list: C468783:H2AX protein, human; D006657:Histones