Department of Hematology and Blood Transfusion, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran.
Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
J Cell Physiol. 2020 Oct;235(10):6404-6423. doi: 10.1002/jcp.29642. Epub 2020 Feb 13.
Hematopoietic stem cells (HSCs) are quiescent cells with self-renewal capacity and potential multilineage development. Various molecular regulatory mechanisms such as epigenetic modifications and transcription factor (TF) networks play crucial roles in establishing a balance between self-renewal and differentiation of HSCs. Histone/DNA methylations are important epigenetic modifications involved in transcriptional regulation of specific lineage HSCs via controlling chromatin structure and accessibility of DNA. Also, TFs contribute to either facilitation or inhibition of gene expression through binding to enhancer or promoter regions of DNA. As a result, epigenetic factors and TFs regulate the activation or repression of HSCs genes, playing a central role in normal hematopoiesis. Given the importance of histone/DNA methylation and TFs in gene expression regulation, their aberrations, including changes in HSCs-related methylation of histone/DNA and TFs (e.g., CCAAT-enhancer-binding protein α, phosphatase and tensin homolog deleted on the chromosome 10, Runt-related transcription factor 1, signal transducers and activators of transcription, and RAS family proteins) could disrupt HSCs fate. Herewith, we summarize how dysregulations in the expression of genes related to self-renewal, proliferation, and differentiation of HSCs caused by changes in epigenetic modifications and transcriptional networks lead to clonal expansion and leukemic transformation.
造血干细胞（HSCs）是具有自我更新能力和潜在多谱系分化能力的静止细胞。各种分子调控机制，如表观遗传修饰和转录因子（TF）网络，在维持 HSCs 的自我更新和分化平衡中起着至关重要的作用。组蛋白/DNA 甲基化是一种重要的表观遗传修饰，通过控制染色质结构和 DNA 的可及性，参与特定谱系 HSCs 的转录调控。此外，TF 通过与 DNA 的增强子或启动子区域结合，促进或抑制基因表达。因此，表观遗传因子和 TF 调节 HSCs 基因的激活或抑制，在正常造血中发挥核心作用。鉴于组蛋白/DNA 甲基化和 TF 在基因表达调控中的重要性，它们的异常，包括 HSCs 相关的组蛋白/DNA 和 TF 甲基化（如 CCAAT 增强子结合蛋白α、染色体 10 上缺失的磷酸酶和张力蛋白同源物、 runt 相关转录因子 1、信号转导和转录激活因子和 RAS 家族蛋白）的改变，可能破坏 HSCs 的命运。在此，我们总结了表观遗传修饰和转录网络中基因表达的失调如何导致 HSCs 自我更新、增殖和分化相关基因的失调，从而导致克隆扩张和白血病转化。
