FZR1 has been implicated as a master regulator of the cell cycle and quiescence, but its roles and molecular mechanisms in the pathogenesis of severe aplastic anemia (SAA) are unclear. Here, we report that FZR1 is downregulated in SAA HSCs compared with healthy control and is associated with decreased quiescence of HSC. Haploinsufficiency of Fzr1 shows impaired quiescence and self-renewal ability of HSC in two Fzr1 heterozygous knockout mouse models. Mechanistically, FZR1 insufficiency inhibits the ubiquitination of RUNX1 protein at lysine 125, leading to the accumulation of RUNX1 protein, which disturbs the quiescence of HSCs in SAA patients. Moreover, downregulation of Runx1 reversed the loss of quiescence and impaired long-term self-renew ability in Fzr1^+/− HSCs in vivo and impaired repopulation capacity in BM from SAA patients in vitro. Our findings, therefore, raise the possibility of a decisive role of the FZR1-RUNX1 pathway in the pathogenesis of SAA via deregulation of HSC quiescence.

FZR1 被认为是细胞周期和静止的主要调节因子，但其在严重再生障碍性贫血 (SAA) 发病机制中的作用和分子机制尚不清楚。在这里，我们报告说，与健康对照相比，SAA HSC 中的 FZR1 下调，并且与 HSC 的静止减少有关。在两种Fzr1杂合基因敲除小鼠模型中，Fzr1 的单倍体不足显示 HSC 的静止和自我更新能力受损。从机制上讲，FZR1 不足会抑制 RUNX1 蛋白在 125 位赖氨酸的泛素化，导致 RUNX1 蛋白的积累，从而扰乱 SAA 患者 HSCs 的静止。此外，Runx1 的下调逆转了Fzr1中静止状态的丧失和长期自我更新能力受损^+/-体内的 HSCs 和体外 SAA 患者 BM 的再增殖能力受损。因此，我们的研究结果提高了 FZR1-RUNX1 通路通过 HSC 静止失调在 SAA 发病机制中起决定性作用的可能性。