Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
Cxcr4-haploinsufficient bone marrow transplantation corrects leukopenia in an unconditioned WHIM syndrome model
Ji-Liang Gao, … , David H. McDermott, Philip M. Murphy
Ji-Liang Gao, … , David H. McDermott, Philip M. Murphy
Published May 1, 2018
Citation Information: J Clin Invest. 2018;128(8):3312-3318. https://doi.org/10.1172/JCI120375.
View: Text | PDF
Concise Communication Immunology Stem cells

Cxcr4-haploinsufficient bone marrow transplantation corrects leukopenia in an unconditioned WHIM syndrome model

  • Text
  • PDF
Abstract

For gene therapy of gain-of-function autosomal dominant diseases, either correcting or deleting the disease allele is potentially curative. To test whether there may be an advantage of one approach over the other for WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome — a primary immunodeficiency disorder caused by gain-of-function autosomal dominant mutations in chemokine receptor CXCR4 — we performed competitive transplantation experiments using both lethally irradiated WT (Cxcr4+/+) and unconditioned WHIM (Cxcr4+/w) recipient mice. In both models, hematopoietic reconstitution was markedly superior using BM cells from donors hemizygous for Cxcr4 (Cxcr4+/o) compared with BM cells from Cxcr4+/+ donors. Remarkably, only approximately 6% Cxcr4+/o hematopoietic stem cell (HSC) chimerism after transplantation in unconditioned Cxcr4+/w recipient BM supported more than 70% long-term donor myeloid chimerism in blood and corrected myeloid cell deficiency in blood. Donor Cxcr4+/o HSCs differentiated normally and did not undergo exhaustion as late as 465 days after transplantation. Thus, disease allele deletion resulting in Cxcr4 haploinsufficiency was superior to disease allele repair in a mouse model of gene therapy for WHIM syndrome, allowing correction of leukopenia without recipient conditioning.

Authors

Ji-Liang Gao, Erin Yim, Marie Siwicki, Alexander Yang, Qian Liu, Ari Azani, Albert Owusu-Ansah, David H. McDermott, Philip M. Murphy

×

Figure 4

Low-level Cxcr4+/o HSC engraftment after BM transplantation is sufficient to correct leukopenia in unconditioned WHIM mice.

Options: View larger image (or click on image) Download as PowerPoint
Low-level Cxcr4+/o HSC engraftment after BM transplantation is sufficien...
(A) Competitive model. BM cells (107) from each of the indicated donors were mixed (final donor BM cell ratio was 47:53, Cxcr4+/o/Cxcr4+/w, Supplemental Figure 7) and transplanted into each unconditioned Cxcr4+/w mouse. Experiment design is shown on the upper left. Recipient mice were euthanized on day 385 after transplantation for mature leukocyte subset analysis in blood and BM, and HSC and HPC analysis in BM. (B) Noncompetitive model. Total BM cells (5 × 107) from each of the indicated donors were transplanted separately into unconditioned Cxcr4+/w mice. Experiment design is shown on the upper left. Mice were euthanized on day 348 after transplantation for mature leukocyte subset analysis in blood and BM, and HSC and HPC analysis in BM. For both A and B, data are the percentage (mean ± SEM) of total cells contributed by the indicated donor (Cxcr4 genotype abbreviated as +/o or +/w) for each indicated HSC/HPC subset in BM and mature leukocyte subset in BM and blood (n = 5 mice per data point). **P < 0.01; ***P < 0.005; ****P < 0.001, Student’s t test. NS, not significant.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts