Fanconi anemia (FA) is a bone marrow failure (BMF) syndrome that arises from mutations in a network of FA genes essential for DNA interstrand crosslink (ICL) repair and replication stress tolerance. While allogeneic stem cell transplantation can replace defective HSCs, interventions to mitigate HSC defects in FA do not exist. Remarkably, we reveal here that Lnk (Sh2b3) deficiency restores HSC function in Fancd2^-/- mice. Lnk deficiency does not impact ICL repair, but instead stabilizes stalled replication forks in a manner, in part, dependent upon alleviating blocks to cytokine-mediated JAK2 signaling. Lnk deficiency restores proliferation and survival of Fancd2^-/- HSCs, while reducing replication stress and genomic instability. Furthermore, deletion of LNK in human FA-like HSCs promotes clonogenic growth. These findings highlight a new role for cytokine/JAK signaling in promoting replication fork stability, illuminate replication stress as a major underlying origin of BMF in FA, and have strong therapeutic implications.

中文翻译：

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Lnk / Sh2b3缺乏症可恢复Fancd2缺乏症的Fanconi贫血中的造血干细胞功能和基因组完整性。

范可尼贫血（FA）是一种骨髓衰竭（BMF）综合征，由DNA链间交联（ICL）修复和复制应激耐受性所必需的FA基因网络中的突变引起。尽管同种异体干细胞移植可以替代有缺陷的HSC，但尚不存在减轻FA中HSC缺陷的干预措施。值得注意的是，我们在这里揭示Lnk（Sh2b3）缺陷可恢复Fancd2 ^-/-小鼠的HSC功能。Lnk缺乏症不影响ICL修复，而是以部分依赖于减轻对细胞因子介导的JAK2信号传导的阻滞的方式稳定停滞的复制叉。Lnk缺乏恢复Fancd2的增殖和生存^-/-HSC，同时减少复制压力和基因组不稳定性。此外，在人FA样HSC中LNK的缺失促进克隆形成生长。这些发现突显了细胞因子/ JAK信号传导在促进复制叉稳定性方面的新作用，阐明复制压力是FA中BMF的主要潜在起源，并具有很强的治疗意义。