Program: Oral and Poster Abstracts
Session: 701. Experimental Transplantation: Basic Biology, Engraftment and Disease Activity: Poster II
Methods: Mouse models of CXCR4 haploinsufficiency (Cxcr4+/o) and WHIMS (Cxcr4+/S338X) were used in competitive bone marrow repopulation experiments transplanting whole bone marrow cells or purified HSC. Recipient mice were treated with / without lethal irradiation prior to transplant. Genome editing with TALENs and CRISPR-Cas9 technology was used to target CXCR4 for deletion in human cell lines.
Results: Cxcr4 haploinsufficiency markedly enhanced HSC engraftment potential in recipient WHIM mice whether the donor HSC were purified from whole bone marrow cells or not, and whether the recipient was conditioned by lethal irradiation or not. Enhanced engraftment by Cxcr4 haploinsufficient donor HSC also occurred in wild-type mouse recipients, but to a lesser extent, and was also HSC intrinsic. Genome editing experiments have been successful at deleting one or both copies of CXCR4 in human cell lines in up to 40% of treated cells, and in reducing CXCR4 surface expression.
Conclusion: While CXCR4 was already understood to be important in HSC biology, this patient and subsequent murine experiments have proven that the gene dosage of CXCR4 is a critical factor affecting HSC engraftment. Genome editing is a promising technology for deleting one copy of CXCR4, ideally the WHIM allele, in autologous HSC as a strategy to cure WHIM syndrome.
Disclosures: McDermott: US National Institutes of Health: Employment , Patents & Royalties: pending . Jacobs: US National Institutes of Health: Employment , Patents & Royalties: pending . Liu: US National Institutes of Health: Employment , Patents & Royalties: pending . Gao: US National Institutes of Health: Employment , Patents & Royalties: pending . Murphy: US National Institutes of Health: Employment , Patents & Royalties: pending .
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