Cxcr4 haploinsufficiency enhances hematopoietic stem cell engraftment
Thursday, September 17, 2015 — Poster Session II
- E Yim
- M Siwicki
- J-L Gao
- PM Murphy
The chemokine receptor CXCR4 plays an important role in homing, retention, and quiescence of hematopoietic stem cells (HSCs) in the bone marrow (BM). Previously, a patient designated ‘WHIM-09’ with WHIM syndrome, a primary immunodeficiency caused by gain-of-function mutations of CXCR4, was found to have been spontaneously cured by chromothripsis (chromosome shattering). The mutant allele CXCR4 (R334X) and one copy of 163 other genes on chromosome 2 were deleted presumably in a single HSC, which then repopulated the patient’s BM. To determine whether CXCR4 hemizygosity per se confers selective engraftment advantage of HSCs, we performed competitive BM repopulation studies using donor cells of increasing stem cell purity and recipients from a WHIM syndrome mouse model (Cxcr4+/S338X), hemizygous Cxcr4 mice (Cxcr4+/o), and wild-type mice (Cxcr4+/+). In these competitive transplantation assays, hemizygous HSCs displayed enhanced proliferation and sustained myeloid reconstitution compared to HSCs from either wild type or WHIM mice. Our findings 1) indicate that Cxcr4 haploinsufficiency enhances HSC engraftment in this system, 2) provide a potential explanation for chromothriptic cure of WHIM syndrome in patient WHIM-09, and 3) suggest that inducing CXCR4 haploinsufficiency by gene editing may facilitate HSC engraftment in gene therapy and other HSC transplantation applications.
Category: Stem Cell Biology