Division of Hematopathology, Department of Pathology and Laboratory Medicine, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA.
Department of Cell Systems and Anatomy, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
J Hematol Oncol. 2022 Sep 6;15(1):127. doi: 10.1186/s13045-022-01336-x.
Myeloid malignancies develop through the accumulation of genetic and epigenetic alterations that dysregulate hematopoietic stem cell (HSC) self-renewal, stimulate HSC proliferation and result in differentiation defects. The polycomb group (PcG) and trithorax group (TrxG) of epigenetic regulators act antagonistically to regulate the expression of genes key to stem cell functions. The genes encoding these proteins, and the proteins that interact with them or affect their occupancy at chromatin, are frequently mutated in myeloid malignancies. PcG and TrxG proteins are regulated by Enhancers of Trithorax and Polycomb (ETP) proteins. ASXL1 and ASXL2 are ETP proteins that assemble chromatin modification complexes and transcription factors. ASXL1 mutations frequently occur in myeloid malignancies and are associated with a poor prognosis, whereas ASXL2 mutations frequently occur in AML with t(8;21)/RUNX1-RUNX1T1 and less frequently in other subtypes of myeloid malignancies. Herein, we review the role of ASXL1 and ASXL2 in normal and malignant hematopoiesis by summarizing the findings of mouse model systems and discussing their underlying molecular mechanisms.
髓系恶性肿瘤的发生是通过遗传和表观遗传改变的积累，这些改变失调造血干细胞（HSC）自我更新，刺激 HSC 增殖，并导致分化缺陷。表观遗传调节剂的 Polycomb 组（PcG）和 trithorax 组（TrxG）拮抗作用调节对干细胞功能至关重要的基因的表达。编码这些蛋白的基因，以及与它们相互作用或影响它们在染色质上占据的蛋白，在髓系恶性肿瘤中经常发生突变。PcG 和 TrxG 蛋白受 Enhancers of Trithorax 和 Polycomb (ETP) 蛋白的调控。ASXL1 和 ASXL2 是 ETP 蛋白，它们组装染色质修饰复合物和转录因子。ASXL1 突变经常发生在髓系恶性肿瘤中，并与预后不良相关，而 ASXL2 突变经常发生在伴有 t(8;21)/RUNX1-RUNX1T1 的 AML 中，在其他髓系恶性肿瘤中较少发生。本文通过总结小鼠模型系统的研究结果，讨论其潜在的分子机制，综述了 ASXL1 和 ASXL2 在正常和恶性造血中的作用。
