Lnk/Sh2b3 deficiency restores hematopoietic stem cell function and genome integrity in Fancd 2 deficient Fanconi anemia

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 stresstolerance. 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 replicationforks 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 stressand 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 replicationfork stability, illuminate replication stressas a major underlying origin of BMF in FA, and have strong therapeutic implications.