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WHIM syndrome–linked CXCR4 mutations impair lymphoid progenitor specification in mice

ABSTRACT: Both cell-intrinsic cues and niche-derived cell-extrinsic cues drive lineage the specification of hematopoietic multipotent progenitors (MPPs) in the bone marrow, comprising multipotent MPP1 cells and lineage-restricted MMP2, MPP3, and MPP4 cells. WHIM syndrome is a rare congenital immunodeficiency caused by gain-of-function mutations in the gene encoding the chemokine receptor CXCR4 and characterized by an increase in the number of myeloid cells that are produced in but fail to exit from the bone marrow. Here, we found that CXCR4 signaling regulated the localization and fate of MPPs. Knock-in mice bearing a WHIM syndrome–associated CXCR4 mutation phenocopied the myeloid-skewing of bone marrow in patients. Myeloid rewiring of lymphoid-primed MPPs (MPP4s) in the mice was associated with enhanced mechanistic target of rapamycin (mTOR) signaling and overactive Oxphos metabolism. The fate of these MPP4 cells was also affected by molecular changes established at the MPP1 level. Mutant MPP4 displayed altered localization in the bone marrow relative to perivascular structures, suggesting that extrinsic cues also contribute to their myeloid skewing. Chronic treatment with the CXCR4 antagonist AMD3100 or the mTOR inhibitor Rapamycin rescued the lymphoid capacities of mutant progenitors including MPP4, demonstrating a pivotal role for the CXCR4-mTOR axis in regulating MPP4 fate. Our study thus provides mechanistic insights into how CXCR4 signaling regulates the lymphoid potential of MPPs.

ORGANISM(S): Mus musculus

PROVIDER: GSE271225 | GEO | 2025/01/22

REPOSITORIES: GEO

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Project description:We are studying the natural history, pathogenesis and treatment of patients with WHIM syndrome, an immunodeficiency disorder characterized by warts, hypogammaglobulinemia, recurrent infections and neutropenia usually due to autosomal dominant gain-of-function mutations in chemokine receptor CXCR4. We have identified a patient born with WHIM syndrome and the WHIM mutation CXCR4R334X who has been disease-free for 20 years and who lacks CXCR4R334X in myeloid cells, the cells that drive disease manifestations. She is a genetic and hematopoietic mosaic, since she still has the mutation in lymphoid cells and non-hematopoietic cells. Cytogenetics and microarray analysis revealed that the mechanism of loss of the mutation was deletion of the mutant allele from one copy of chromosome 2. Whole genome sequencing of patient neutrophil and skin fibroblast genomic DNA revealed that the mechanism of deletion was chromothripsis, a process of chromosome shattering resulting in deletions and rearrangements of the non-deleted chromosomal segments. In the patient, this process evidently occurred in a single hematopoietic stem cell (HSC), resulting in deletion of the disease allele CXCR4R334X and one copy of 163 other genes on chromosome 2. This HSC evidently acquired a growth advantage and repopulated the HSC population and the myeloid lineage. Consistent with this, studies using gene targeted mice in competitive bone marrow transplantation experiments revealed that selective Cxcr4 haploinsufficiency (inactivation of one copy of Cxcr4 and not of any other genes) was sufficient to confer a strong engraftment advantage over bone marrow cells from wild type mice as well as bone marrow cells from a mouse model of WHIM syndrome. These results suggest that CXCR4 knockdown may be a useful strategy to enhance bone marrow engraftment in the absence of toxic bone marrow conditioning regimens.

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WHIM syndrome–linked CXCR4 mutations impair lymphoid progenitor specification in mice

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