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Chromothriptic cure of WHIM syndrome: Implications for bone marrow transplantation.

ABSTRACT: We recently reported a 59 year old female, designated WHIM-09, who was born with the rare immunodeficiency disease WHIM syndrome but underwent spontaneous phenotypic reversion as an adult. The causative WHIM mutation CXCR4 (R334X) was absent in her myeloid and erythroid lineage, but present in her lymphoid lineage and in epithelial cells, defining her as a somatic genetic mosaic. Genomic and hematologic analysis revealed chromothripsis (chromosome shattering) on one copy of chromosome 2, which deleted 164 genes including CXCR4 (R334X) in a single haematopoietic stem cell (HSC) (Fig. 1). Experiments in mice indicated that deleting one copy of Cxcr4 is sufficient to confer a selective advantage for engraftment of transplanted HSCs, suggesting a mechanism for clinical cure in WHIM-09. Genome editing may allow autologous transplantation of HSCs lacking one copy of CXCR4 without bone marrow conditioning as a general cure strategy in WHIM syndrome, safely recapitulating the outcome in patient WHIM-09. Figure 1.Chromothripsis (chromosomal shattering) resulted in clinical cure of a patient with a rare immunodeficiency (WHIM syndrome) by deleting the mutant copy of CXCR4.

SUBMITTER: McDermott DH

PROVIDER: S-EPMC4588533 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Chromothriptic cure of WHIM syndrome: Implications for bone marrow transplantation.

McDermott David H DH Gao Ji-Liang JL Murphy Philip M PM

Rare diseases (Austin, Tex.) 20150811 1

We recently reported a 59 year old female, designated WHIM-09, who was born with the rare immunodeficiency disease WHIM syndrome but underwent spontaneous phenotypic reversion as an adult. The causative WHIM mutation CXCR4 (R334X) was absent in her myeloid and erythroid lineage, but present in her lymphoid lineage and in epithelial cells, defining her as a somatic genetic mosaic. Genomic and hematologic analysis revealed chromothripsis (chromosome shattering) on one copy of chromosome 2, which d ...[more]

PMID: 26459672

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Project description:BackgroundNuclear accidents and terrorism presents a serious threat for mass casualty. While bone-marrow transplantation might mitigate hematopoietic syndrome, currently there are no approved medical countermeasures to alleviate radiation-induced gastrointestinal syndrome (RIGS), resulting from direct cytocidal effects on intestinal stem cells (ISC) and crypt stromal cells. We examined whether bone marrow-derived adherent stromal cell transplantation (BMSCT) could restitute irradiated intestinal stem cells niche and mitigate radiation-induced gastrointestinal syndrome.Methodology/principal findingsAutologous bone marrow was cultured in mesenchymal basal medium and adherent cells were harvested for transplantation to C57Bl6 mice, 24 and 72 hours after lethal whole body irradiation (10.4 Gy) or abdominal irradiation (16-20 Gy) in a single fraction. Mesenchymal, endothelial and myeloid population were characterized by flow cytometry. Intestinal crypt regeneration and absorptive function was assessed by histopathology and xylose absorption assay, respectively. In contrast to 100% mortality in irradiated controls, BMSCT mitigated RIGS and rescued mice from radiation lethality after 18 Gy of abdominal irradiation or 10.4 Gy whole body irradiation with 100% survival (p<0.0007 and p<0.0009 respectively) beyond 25 days. Transplantation of enriched myeloid and non-myeloid fractions failed to improve survival. BMASCT induced ISC regeneration, restitution of the ISC niche and xylose absorption. Serum levels of intestinal radioprotective factors, such as, R-Spondin1, KGF, PDGF and FGF2, and anti-inflammatory cytokines were elevated, while inflammatory cytokines were down regulated.Conclusion/significanceMitigation of lethal intestinal injury, following high doses of irradiation, can be achieved by intravenous transplantation of marrow-derived stromal cells, including mesenchymal, endothelial and macrophage cell population. BMASCT increases blood levels of intestinal growth factors and induces regeneration of the irradiated host ISC niche, thus providing a platform to discover potential radiation mitigators and protectors for acute radiation syndromes and chemo-radiation therapy of abdominal malignancies.

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Chromothriptic cure of WHIM syndrome: Implications for bone marrow transplantation.

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Chromothriptic cure of WHIM syndrome: Implications for bone marrow transplantation.

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