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Enhancement of stem cell engraftment on a WHIM
Hal E. Broxmeyer
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Address correspondence to: Hal E. Broxmeyer, Indiana University School of Medicine, Department of Microbiology and Immunology, 950 West Walnut Street, R2-302, Indianapolis, Indiana 46202-5181, USA. Phone: 317.274.7510; Email: hbroxmey@iupui.edu.
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Published June 25, 2018 - More info
J Clin Invest. 2018;128(8):3240–3242. https://doi.org/10.1172/JCI121857.
Copyright © 2018, American Society for Clinical Investigation
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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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Introduction
Chemokine receptor CXCR4 and one of its two ligands, CXCL12 (also known as stromal cell derived factor 1 [SDF-1]), are involved in the migration, homing, mobilization, and survival of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) (1). The genetic disorder WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome manifests as a primary immunodeficiency and involves an autosomal dominant gain-of-function CXCR4 mutation. In this issue, Gao et al. (2) provide a follow-up on previous studies that have advanced the understanding of the pathophysiology and treatment of WHIM and a role for CXCR4 in the disease. Allogeneic BM transplantation has been used to cure several patients with WHIM (3, 4), and an antagonist of CXCR4 (5), originally called AMD3100 and more recently termed plerixafor (Mozobil, Sanofi), is currently being evaluated in a clinical trial for this disorder (6–8). In their previous study, McDermott et al. reported on one patient with WHIM in whom chromothripsis (known as chromosome shattering) resulted in spontaneous deletion of the WHIM allele in a single HSC and subsequent cure of WHIM syndrome in the individual (9). While 164 genes were deleted by this chromothriptic event, Gao et al. have now focused on CXCR4 and found a selective growth advantage of Cxcr4-haploinsufficient (Cxcr4+/o) mouse BM HSCs that yielded almost total chimerism of myeloid cells in a congenic mouse competitive transplant setting (2). Cxcr4+/o BM cells resulted in stable long-term engraftment beyond that of BM from either WHIM model mice (Cxcr4+/w) or WT Cxcr4+/+ animals in the setting of competitive transplantation following lethal irradiation of congenic mouse recipients. Moreover, recipient Cxcr4+/w WHIM mice were able to accept the engraftment of Cxcr4+/o HSCs without any conditioning, and a small percentage of donor Cxcr4+/o HSCs were able to support more than 70% long-term chimerism of myeloid cells in unconditioned Cxcr4+/w mice, resulting in correction of the blood myeloid deficiency in Cxcr4+/w WHIM mice (Figure 1A).
Figure 1Modulation of CXCR4 and associated pathways may enhance HSC engraftment. (A) Summary of some findings of Gao et al. (2). Engraftment of WT (Cxcr4+/+), hemizygous (Cxcr4+/o), or WHIM (Cxcr4+/w) donor cells in either lethally irradiated Cxcr4+/+ mice or in unconditioned Cxcr4+/+ or Cxcr4+/w recipients. Hemizygous Cxcr4 cells have markedly increased engraftment compared with cells from WT or WHIM mice. (B) Several additional possibilities to enhance engraftment of HSCs in the context of WHIM and other nonmalignant or malignant disorders. These include HSC collection under hypoxic conditions and strategies to modify CXCR4, CXC12, and DPP4 in the bone marrow microenvironment of recipients. ↑, denotes engraftment, ↑↑, greater engraftment, ↑↑↑, even greater engraftment, and X, no engraftment. Details are provided in the text of this commentary.
Based on these data, Gao et al. suggested future gene editing possibilities to delete the WHIM allele in donor cells for curative autologous transplantation that would not require conditioning of the patient. In fact, the actual implications of these studies may go well beyond selective correction of the clinical WHIM syndrome, as engraftment involves the homing characteristics of donor cells and the nurturing capacity of the BM microenvironment. Additional translational aspects of the improved engraftment of Cxcr4-haplosufficient HSCs that extend beyond WHIM (Figure 1B) are discussed below.
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