@article{10.1172/jci.insight.132140, author = {Ji-Liang Gao AND Albert Owusu-Ansah AND Andrea Paun AND Kimberly Beacht AND Erin Yim AND Marie Siwicki AND Alexander Yang AND Qian Liu AND David H. McDermott AND Philip M. Murphy}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Low-level Cxcr4-haploinsufficient HSC engraftment is sufficient to correct leukopenia in WHIM syndrome mice}, year = {2019}, month = {12}, volume = {4}, url = {https://insight.jci.org/articles/view/132140}, abstract = {Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome immunodeficiency is caused by autosomal dominant gain-of-function mutations in chemokine receptor CXCR4. Patient WHIM-09 was spontaneously cured by chromothriptic deletion of 1 copy of 164 genes, including the CXCR4WHIM allele, presumably in a single hematopoietic stem cell (HSC) that repopulated HSCs and the myeloid lineage. Testing the specific contribution of CXCR4 hemizygosity to her cure, we previously demonstrated enhanced engraftment of Cxcr4+/o HSCs after transplantation in WHIM (Cxcr4+/w) model mice, but the potency was not quantitated. We now report graded-dose competitive transplantation experiments using lethally irradiated Cxcr4+/+ recipients in which mixed BM cells containing approximately 5 Cxcr4+/o HSCs and a 100-fold excess of Cxcr4+/w HSCs achieved durable 50% Cxcr4+/o myeloid and B cell chimerism in blood and approximately 20% Cxcr4+/o HSC chimerism in BM. In Cxcr4+/o/Cxcr4+/w parabiotic mice, we observed 80%–100% Cxcr4+/o myeloid and lymphoid chimerism in the blood and 15% Cxcr4+/o HSC chimerism in BM from the Cxcr4+/w parabiont, which was durable after separation from the Cxcr4+/o parabiont. Thus, CXCR4 haploinsufficiency likely significantly contributed to the selective repopulation of HSCs and the myeloid lineage from a single chromothriptic HSC in WHIM-09. Moreover, the results suggest that WHIM allele silencing of patient HSCs is a viable gene therapy strategy.}, number = {24}, doi = {10.1172/jci.insight.132140}, url = {https://doi.org/10.1172/jci.insight.132140}, }