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

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

doi:10.1038/srep19589

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

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

Toxicology and Cancer Biology

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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.

Original language	English
Article number	19589
Journal	Scientific Reports
Volume	6
DOIs	https://doi.org/10.1038/srep19589
State	Published - Jan 21 2016

Bibliographical note

Funding Information:
We thank Dr. Lin Li of the Mouse Histology and Phenotyping Laboratory of Northwestern University for help with mouse histology, and Bella Shmaltsuyeva of the Pathology Core Facility of Northwestern University for help with H2AX immunohistochemistry. This work is supported by the National Institutes of Health Pathway to Independence award (R00HL102154), the National Institute of Diabetes and Digestive and Kidney Diseases grant (R01DK102718), and the American Society for Hematology scholar award to P.J.

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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.",

author = "Baobing Zhao and Tan, {Timothy L.} and Yang Mei and Jing Yang and Yiting Yu and Amit Verma and Ying Liang and Juehua Gao and Peng Ji",

note = "Funding Information: We thank Dr. Lin Li of the Mouse Histology and Phenotyping Laboratory of Northwestern University for help with mouse histology, and Bella Shmaltsuyeva of the Pathology Core Facility of Northwestern University for help with H2AX immunohistochemistry. This work is supported by the National Institutes of Health Pathway to Independence award (R00HL102154), the National Institute of Diabetes and Digestive and Kidney Diseases grant (R01DK102718), and the American Society for Hematology scholar award to P.J.",

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AU - Zhao, Baobing

AU - Tan, Timothy L.

AU - Mei, Yang

AU - Yang, Jing

AU - Yu, Yiting

AU - Verma, Amit

AU - Liang, Ying

AU - Gao, Juehua

AU - Ji, Peng

N1 - Funding Information: We thank Dr. Lin Li of the Mouse Histology and Phenotyping Laboratory of Northwestern University for help with mouse histology, and Bella Shmaltsuyeva of the Pathology Core Facility of Northwestern University for help with H2AX immunohistochemistry. This work is supported by the National Institutes of Health Pathway to Independence award (R00HL102154), the National Institute of Diabetes and Digestive and Kidney Diseases grant (R01DK102718), and the American Society for Hematology scholar award to P.J.

PY - 2016/1/21

Y1 - 2016/1/21

N2 - 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.

AB - 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.

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

Abstract

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