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

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.