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Rescue Hematopoietic Stem and Progenitor Cell Functions in Bone Marrow Failure Syndromes

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Technical Report,01 Aug 2018,31 Jul 2019

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Childrens Hospital of Philadelphia Philadelphia United States

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Fanconi Anemia FA is one of the most common inherited bone marrow failure syndromes. If left untreated, 90 percent of children experience severe bone marrow failure or leukemia. There are few therapeutic options besides stem cell transplant SCT, but the latter is associated with high risks of morbidity and mortality. The failure to appropriately deal with damaged genes especially hurts one type of cells in the body, called blood stem cells that are located in the bone marrow. These stem cells normally replenish blood supply for a lifetime but in the case of FA undergo attrition and finally complete exhaustion leading to a condition called bone marrow failure. Our work offers a new strategy by which the stem cell defect in FA might be overcome. Specifically, we discovered a gene, called SH2B3LNK, which when disrupted leads to the expansion of blood stem cells in animal models including normal and FA animals. We identified the mechanisms by which SH2B3 deficiency improves FA HSCs, is not due to a correction of a particular type of DNA repair. Rather, SH2B3 deficiency enhances replication stress mitigation, decreases replication associated DNA damages, in part through cytokineJAK signaling. In the past year, we have successfully explored the potential of LNK inhibition in expanding human hematopoietic stem cells in vitro and in vivo, and have begun to study LNK inhibition in restoring progenitor cells from FA patient cells.

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  • Medicine and Medical Research

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