Lnk/Sh2b3 deficiency restores hematopoietic stem cell function and genome integrity in Fancd2 deficient Fanconi anemia

Joanna Balcerek, Jing Jiang, Yang Li, Qinqin Jiang, Nicholas Holdreith, Brijendra Singh, Vemika Chandra, Kaosheng Lv, Jian-gang Ren, Krasimira Rozenova, Weihua Li, Roger A. Greenberg and Wei Tong ()
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Joanna Balcerek: Children′s Hospital of Philadelphia
Jing Jiang: Children′s Hospital of Philadelphia
Yang Li: Children′s Hospital of Philadelphia
Qinqin Jiang: Abramson Cancer Research Institute and Basser Center for BRCA, and Perelman School of Medicine at the University of Pennsylvania
Nicholas Holdreith: Children′s Hospital of Philadelphia
Brijendra Singh: Children′s Hospital of Philadelphia
Vemika Chandra: Children′s Hospital of Philadelphia
Kaosheng Lv: Children′s Hospital of Philadelphia
Jian-gang Ren: Children′s Hospital of Philadelphia
Krasimira Rozenova: Children′s Hospital of Philadelphia
Weihua Li: Abramson Cancer Research Institute and Basser Center for BRCA, and Perelman School of Medicine at the University of Pennsylvania
Roger A. Greenberg: Abramson Cancer Research Institute and Basser Center for BRCA, and Perelman School of Medicine at the University of Pennsylvania
Wei Tong: Children′s Hospital of Philadelphia

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-06380-1

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