Extracellular Vesicles Impose Quiescence on Residual Hematopoietic Stem Cells in the Leukemic Niche

Progressive remodeling of the bone marrow microenvironment is recognized as an integral aspect of leukemogenesis. Expanding Acute myeloid Leukemia (AML) clones not only alter stroma composition, but actively constrain hematopoiesis, representing a significant source of patient morbidity and mortality. Recent studies revealed the surprising resistance of long-term hematopoietic stem cells (LT-HSC) to elimination from the leukemic niche. Here we examine the fate and function of residual LT-HSC in the BM of murine xenografts with emphasis on the role of AML-derived Extracellular Vesicles (EV). AML-EV rapidly enter HSC and their trafficking elicits protein synthesis suppression and LT-HSC quiescence. Mechanistically, AML-EV transfer a panel of miRNA, including miR-1246, that target the mTOR subunit Raptor, causing ribosomal protein S6 hypo-phosphorylation which in turn impairs protein synthesis in LT-HSC. While HSC functionally recover from quiescence upon transplantation to an AML-naive environment, they maintain relative gains in repopulation capacity. These phenotypic changes are accompanied by DNA double-strand breaks and evidence of a sustained DNA-damage response. In sum, AML-EV contribute to niche-dependent, reversible quiescence and elicit persisting DNA-damage in LT-HSC.

骨髓微环境的进行性重塑被认为是白血病发生（leukemogenesis）的核心环节。扩增的急性髓系白血病（Acute myeloid Leukemia, AML）克隆不仅会改变骨髓基质的细胞组成，还会主动抑制造血功能，这是导致患者发病与死亡的重要诱因。近期研究发现，长期造血干细胞（long-term hematopoietic stem cells, LT-HSC）对白血病微环境中的清除过程表现出出人意料的抵抗性。本研究旨在探究小鼠异种移植模型骨髓中残留LT-HSC的命运与功能，重点关注AML来源的细胞外囊泡（Extracellular Vesicles, EV）所发挥的作用。AML-EV可快速进入造血干细胞（HSC），其胞内转运会引发蛋白质合成抑制与LT-HSC静止状态的出现。从机制层面来看，AML-EV会传递一组包含miR-1246在内的微小RNA（microRNA, miRNA），这些miRNA可靶向结合雷帕霉素靶蛋白（mTOR）亚基Raptor，导致核糖体蛋白S6磷酸化水平降低，进而损害LT-HSC内的蛋白质合成功能。当将这些HSC移植至未接触过AML的正常微环境中时，其虽可从静止状态中恢复功能，但仍保留了重建造血能力的相对优势。上述表型变化伴随有DNA双链断裂（DNA double-strand breaks）以及持续的DNA损伤应答（DNA-damage response）相关证据。综上，AML-EV可诱导依赖于微环境的可逆性静止状态，并引发LT-HSC出现持续性DNA损伤。