Bone Marrow Failure
Posted December 5, 2018
Wei Tong, Ph.D., Children's Hospital of Philadelphia
Dr. Wei Tong,
Children's Hospital of Philadelphia
Fanconi anemia (FA) is a rare and fatal inherited blood disorder caused by a mutation in one of 22 FA genes. The network of FA genes is essential for DNA interstrand crosslinks (ICLs) repair, which permits proper DNA replication. Defects in DNA repair have devastating effects on hematopoietic stem cells (HSCs), which are immature cells of the bone marrow that can develop into all the types of circulating blood cells. HSCs typically replenish, but in the case of FA, they gradually diminish and if left untreated, this will lead to severe bone marrow failure, leukemia, and eventual death. Few therapeutic options exist for FA aside from stem cell transplant, which is associated with high risks of morbidity.
Dr. Wei Tong discovered a gene, LNK (also called SH2B3), which encodes the lymphocyte adapter protein, which, when disrupted, leads to the expansion of HSCs in both healthy and FA animal models. With support from a Fiscal Year 2016 Bone Marrow Failure Research Project Idea Development Award, Dr. Tong and her laboratory set out to understand the role of LNK in the maintenance of HSCs, with the hopes of exploiting its mechanism and potentially creating a new therapeutic for treating the fatal disease.
Dr. Tong tested the hypothesis that LNK deficiency would improve HSC defects associated with FA. Her studies showed remarkable results in which deletion of LNK restored HSC progenitor cell function in the FA rodent model to wild-type levels without accelerating neoplastic transformation (or conversion of normal cells into tumor cells). LNK knockout reduced spontaneous DNA damage and genome instability; however, the mechanism by which LNK deficiency restored HSC activity did not appear to be through ICL repair. Instead, LNK deficiency mitigated replication stress associated with FA, this was mediated in part though an increase in the JAK pathway. The JAK pathway is well-known for its role in hematopoiesis (promoting blood formation) and immune response, but Dr. Tong's results reveal a lesser known role for JAK in regulating DNA replication and suppressing DNA damage. Dr. Tong is currently working on the next phase of her project which will involve targeting LNK in human FA patient HSCs to confirm that LNK inhibition will restore growth in human FA.
Dr. Tong's results highlight an important role for the JAK signaling pathway in promoting DNA replication and genome stability in FA. What's more, the JAK pathway is well-known and is already manipulated with drugs for other diseases. This work also represents the first published incident of an investigator successfully reversing FA-associated HSC defects and successfully restoring function and genomic stability to HSC progenitor cells in FA-associated animal models to healthy levels.
Dr. Tong's research offers new targets and treatment strategies for FA and other bone marrow failure diseases. It has uncovered a possible means of restoring function in HSCs without stem cell transplants, thus avoiding the high risks of morbidity and mortality associated with that treatment.
Publication:
Balcerek J, Jiang J, Li Y, et al. 2018. Lnk/Sh2b3 deficiency restores hematopoietic stem cell functions and genome integrity in Fancd2 deficient Fanconi anemia. Nature Comm 9(3915). DOI: 10.1038/s41467-018-06380-1.
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