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.

Oxidative DNA Damage, Inflammatory Signature, and Altered Erythrocytes Properties in Diamond-Blackfan Anemia

“…On the other hand, γ-H2AX in Rps19-deficient cells was less significantly induced (MFI: 7.59 ± 0.57), suggesting a lesser extent of DNA damage. Because γ-H2AX levels dramatically increase during late-stage erythropoiesis [ 17 ], MEL cells induced to erythroid differentiation were not evaluated.…”

Loss of mDia1 causes neutropenia via attenuated CD11b endocytosis and increased neutrophil adhesion to the endothelium

“…Bone marrow transplantation was performed as previously described. 4,10,11 In brief, 2 3 10 6 donor bone marrow cells from 6-to 8-week-old mice were injected retro-orbitally into a lethally irradiated (10 Gy) recipient mouse. The competitive bone marrow transplantation was carried out under the same conditions, except that 1 3 10 6 mDia1 knockout cells harboring GFP were premixed with 1 3 10 6 wild-type cells from their littermate control mice.…”

Histone H2A.X phosphorylation and Caspase-Initiated Chromatin Condensation in late-stage erythropoiesis

“…Loss of histone H2A.X does not completely inhibit erythroid differentiation or prevent all nuclear condensation; H2A.X KO mice are anemic, but they are also viable [ 14 ]. Moreover, in our HUDEP-2 KO models we observed variability between clonal cell lines in the extent to which caspase cleavage was diminished.…”

“…Normal erythroid maturation requires the histone H2A variant, H2A.X [ 14 ]. Loss of histone H2A.X in erythroid cells in mice leads to a decrease in enucleated cells and dyserythropoiesis, along with the appearance of Howell–Jolly bodies, which are nuclear remnants indicative of inefficient enucleation, in mature red blood cells.…”

“…Loss of histone H2A.X in erythroid cells in mice leads to a decrease in enucleated cells and dyserythropoiesis, along with the appearance of Howell–Jolly bodies, which are nuclear remnants indicative of inefficient enucleation, in mature red blood cells. Collectively, these features resemble phenotypes in patients with myelodysplastic syndrome and thus indicate defects in normal erythroid maturation [ 14 ]. While the best studied function of histone H2A.X is its role in amplifying the signal for DNA repair upon phosphorylation of S139 in its C-terminal tail region (H2A.X pS139 or γ-H2A.X), other functions have been described [ 15 – 19 ].…”