Hospital of Philadelphia
Wei Tong, PhD Photo courtesy of Children's
A novel approach can restore hematopoietic stem cell (HSC) function in Fanconi anemia (FA), according to preclinical research published in Nature Communications.
The investigators showed that Lnk (Sh2b3) deficiency restores HSC proliferation and survival in Fancd2-deficient mice.
And it does so, in part, by alleviating blocks to cytokine-mediated JAK2 signaling.
These findings, the researchers wrote, “highlight a new role for cytokine/JAK signaling” and have therapeutic implications for FA.
The investigators noted that FA is caused by mutations in genes that are essential for DNA interstrand crosslink repair and replication stress tolerance.
Allogeneic transplant can replace defective HSCs in patients with FA, the researchers said, but there are no interventions that mitigate defects in HSCs. So the investigators decided to test whether Lnk deficiency ameliorates HSC defects in FA.
Using a model of FA in which mice lacked Fancd2, the researchers inhibited the regulatory protein Sh2b3/Lnk.
The investigators said Lnk deficiency restored the proliferation and survival of Fancd2−/− HSCs while also reducing replication stress and genomic instability. Lnk deficiency did not, however, affect DNA interstrand crosslink repair.
“We expected that inhibiting Lnk would restore the ability of FA cells to repair DNA damage, but this was not the case,” said study author Wei Tong, PhD, of Children’s Hospital of Philadelphia in Pennsylvania.
“Instead, inhibiting Lnk stabilized the stalled replication machinery, allowing affected cells to continue to copy DNA, and to prevent small errors from cascading into a catastrophic failure. The most exciting aspect of this discovery is that Lnk is part of a well-known growth pathway that can be manipulated by existing drugs in other diseases.”
That pathway is the TPO/MPL/JAK2 pathway, which is already targeted by eltrombopag and romiplostin for immune thrombocytopenia and eltrombopag for aplastic anemia.
The researchers plan to continue their work with animal models of FA and Lnk.
“Our ultimate goal is to translate our knowledge into treatments for both Fanconi anemia and for the broader problem of bone marrow failure,” Dr. Tong said.
This research was supported by the National Institutes of Health, the Fanconi Anemia Research Fund, the Department of Defense, the Basser Center for BRCA Team Science Grant, the Leukemia Lymphoma Society Scholar Award, and the Patel Family Award.
The researchers declared no competing interests.