Figure 3.

m⁶A methylation modifications and normal hematopoietic regulation. This image depicts the role of RNA m⁶A methylation in normal human hematopoiesis. (a) The development and differentiation process with respect to human normal hematopoietic stem/progenitor cells (HSPCs) is presented here, i.e., from HSPCs to terminally differentiated erythroid, lymphoid, and myeloid cells; (b) It has revealed that m⁶A modification modulates the normal hematopoietic system. ① METTL3-mediated m⁶A modifications regulate HSPC fate specification via suppressing Notch signaling during early definitive hematopoiesis. ② During the expansion of HSPC in the fetal liver, METTL3 deletion promotes the formation of dsRNA, activates the OAS RNase L and PKR-eIF2a pathways, and upregulates MDA5/RIG-I, resulting in hematopoietic failure. ③ METTL14 is highly expressed during the development of normal CD34⁺ HSPCs cells, and silencing METTL14 facilitates terminal myeloid differentiation of HSPCs cells. ④ In R-2HG-sensitive leukemic cells but not in normal CD34⁺ HSPCs, overexpression of FTO reverses the effect of R-2HG-induced glycolysis inhibition, leading to leukemogenesis in vivo. ⑤ Deficiency of YTHDF2 causes the failure of hematopoietic stem cells during serial transplantation and prolonged activation of pro-inflammatory pathways, ultimately contributing to progressive bone marrow bias. ⑥ YTHDC1 deletion impedes the proliferation and survival of LSCs in vivo, supporting the oncogenic role of YTHDC1 in leukemias (e.g., AML). Abbreviations: HSPCs hematopoietic stem/progenitor cells; MPP multipotent progenitors; LMPP lymphoid-primed multipotential progenitors; CMP common myeloid progenitor; CLP common lymphoid progenitor; GMPs granulocyte/monocyte progenitor; MEPs megakaryocytes/erythroid progenitor; Gn granulocyte; DC dendritic cell; M monocyte; E erythrocyte; NK natural killer cell; EHT endothelial-to-hematopoietic transition; LSCs leukemia stem cells; HE hemogenic endothelial; R-2HG R-2-hydroxyglutarate.