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Cxcr4 haploinsufficiency confers a selective advantage for hematopoietic stem cell engraftment

Friday, September 16, 2016 — Poster Session IV

12:00 p.m. – 1:30 p.m.
FAES Terrace
NIAID
IMMUNO-5

Authors

  • E Yim
  • J-L Gao
  • PM Murphy

Abstract

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 CXCR4R334X and one copy of 163 other genes on chromosome 2 were deleted presumably in a single HSC, which then repopulated the patient’s BM. Competitive BM repopulation studies using donors and recipients from a WHIM syndrome mouse model (Cxcr4+/S338X), hemizygous Cxcr4 mice (Cxcr4+/o), and wild-type mice (Cxcr4+/+) suggest that Cxcr4 hemizygosity confers a selective engraftment advantage for HSC engraftment. In these competitive transplantation assays using irradiated and non-irradiated mice, 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 without conditioning.

Category: Immunology