Hematopoietic stem cell (HSC) attrition is considered the key event underlying progressive BM failure (BMF) in Fanconi anemia (FA), the most frequent inherited BMF disorder in humans. However, despite major advances, how the cellular, biochemical, and molecular alterations reported in FA lead to HSC exhaustion remains poorly understood. Here, we demonstrated in human and mouse cells that loss-of-function of FANCA or FANCC, products of 2 genes affecting more than 80% of FA patients worldwide, is associated with constitutive expression of the transcription factor microphthalmia (MiTF) through the cooperative, unscheduled activation of several stress-signaling pathways, including the SMAD2/3, p38 MAPK, NF-κB, and AKT cascades. We validated the unrestrained Mitf expression downstream of p38 in Fanca^–/– mice, which display hallmarks of hematopoietic stress, including loss of HSC quiescence, DNA damage accumulation in HSCs, and reduced HSC repopulation capacity. Importantly, we demonstrated that shRNA-mediated downregulation of Mitf expression or inhibition of p38 signaling rescued HSC quiescence and prevented DNA damage accumulation. Our data support the hypothesis that HSC attrition in FA is the consequence of defects in the DNA-damage response combined with chronic activation of otherwise transiently activated signaling pathways, which jointly prevent the recovery of HSC quiescence.

中文翻译：

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小眼症转录因子表达导致范可尼贫血的骨髓衰竭

造血干细胞（HSC）损耗被认为是范可尼贫血（FA）（人类最常见的遗传性BMF疾病）中进行性BM衰竭（BMF）的关键事件。然而，尽管取得了重大进展，但FA中报道的细胞，生化和分子改变如何导致HSC衰竭仍知之甚少。在这里，我们证明了在人类和小鼠细胞中，FANCA或FANCC的功能丧失（影响全球80％以上的FA患者的2个基因的产物）与转录因子小眼症（MiTF）的组成型表达有关，通过合作，多种应激信号通路的非计划激活，包括SMAD2 / 3，p38 MAPK，NF-κB和AKT级联反应。我们验证了奔放MITF在P38的下游表达FANCA^{– / –}小鼠，具有造血应激的特征，包括造血干细胞静止性的丧失，造血干细胞中DNA损伤的积累以及造血干细胞的减少。重要的是，我们证明了shRNA介导的Mitf表达下调或p38信号的抑制可以挽救HSC的静止并防止DNA损伤的积累。我们的数据支持以下假说：FA中的HSC损耗是DNA损伤反应缺陷的结果，加上其他方式短暂激活的信号通路的慢性激活，这共同阻止了HSC静止的恢复。