Cxcr4-haploinsufficient bone marrow transplantation corrects leukopenia in an unconditioned WHIM syndrome model
Ji-Liang Gao, Erin Yim, Marie Siwicki, Alexander Yang, Qian Liu, Ari Azani, Albert Owusu-Ansah, David H. McDermott, Philip M. Murphy
Ji-Liang Gao, Erin Yim, Marie Siwicki, Alexander Yang, Qian Liu, Ari Azani, Albert Owusu-Ansah, David H. McDermott, Philip M. Murphy
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Concise Communication Immunology

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

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

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Figure 3

Correction of myeloid cytopenia in unconditioned WHIM mice by congenic Cxcr4+/o BM transplantation.

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Correction of myeloid cytopenia in unconditioned WHIM mice by congenic C...
(A) Cxcr4+/o BM is superior to Cxcr4+/+ BM for establishing durable hematopoietic chimerism in unconditioned congenic Cxcr4+/w recipients. Experiment design is shown on the left of each row of graphs. Donor-derived cell frequencies for each Cxcr4 genotype are shown for the leukocyte subsets indicated. Data are the percentage (mean ± SEM) of total cells for each subset (n = 5–8 mice per data point). Donor genotypes are abbreviated as +/o, +/+, and +/w. See Supplemental Figure 7 for representative flow cytometry plots and transplantation conditions. (B) Correction of myeloid cytopenia. Noncompetitive transplantation of 5 × 107 total BM cells from Cxcr4+/o (red) or Cxcr4+/w (blue) donor mice to unconditioned Cxcr4+/w recipients. Experiment design is shown on the upper left. The lower panels show donor-derived cell frequencies for the leukocyte subsets indicated, presented as the percentage (mean ± SEM) of total cells for each subset (n = 5 mice per data point). Donor genotypes are abbreviated as +/o and +/w. The upper right 3 panels show leukocyte subset counts of total cells, recipient cells, and donor-derived cells at day 120 after transplantation of unconditioned Cxcr4+/w mice receiving Cxcr4+/o (red) or Cxcr4+/w (blue) BM. Dashed lines indicate average values of blood counts for each subset of naive Cxcr4+/+ (red, n = 58) or Cxcr4+/w (blue, n = 38) mice in our colony. Symbols +/o→+/w and +/w→+/w are the abbreviations of Cxcr4+/w mice receiving Cxcr4+/o BM (red) and Cxcr4+/w mice receiving Cxcr4+/w BM (blue), respectively. *P < 0.05; **P < 0.01; ***P < 0.005. Single comparisons, Student’s t test; multiple comparisons, 2-way ANOVA.