H2AX deficiency is associated with erythroid dysplasia and compromised haematopoietic stem cell function.

Baobing Zhao,Amit Verma,Jing Yang,Juehua Gao,Yang Mei,Timothy L Tan,Ying Liang,Yiting Yu,Peng Ji

doi:10.1038/srep19589

Baobing Zhao, Amit Verma + Show 7 more

Open Access

https://doi.org/10.1038/srep19589

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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.

Highlights

H2AX is a histone variant with a major function in the DNA double-strand break (DSB) repair[19,20,21]
Because Howell-Jolly bodies are frequently observed in Myelodysplastic syndromes (MDS) patients, we examined the morphology of bone marrow erythroid cells in H2AX knockout mice
Dysplastic features include nuclear budding and irregular nuclear contour in bone marrow. We found that these features were recapitulated in late-stage erythroblasts of H2AX knockout mice

Summary

Introduction

H2AX is a histone variant with a major function in the DNA double-strand break (DSB) repair[19,20,21]. Upon DSB induced by internal or external stresses, H2AX is phosphorylated at amino acid 139 on its C-terminal tail and accumulates at the DNA damage site[19,22]. Phosphorylated H2AX, called γ -H2AX, further recruits downstream DNA repair proteins such as 53BP1, MDC1, RAD51, BRCA1, and the MRE11/RAD50/NBS1 complex to DSB sites. Mice with H2AX deficiency show chromosomal instability, DSB repair defects, and impaired recruitment of repair proteins to DSB sites[23]. Mice with combined H2AX and TP53 deficiency develop several different cancers, including hematologic malignancies[24]. Together, these studies suggest that loss of H2AX plays a role in the development of myeloid dysplasia. Data from MDS patients further indicate that loss of H2AX could be a mechanism contributing to dyserythropoiesis in MDS

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