Here, we addressed this point using as a paradigm the WHIM Syndrome (WS), a rare immunodeficiency caused by viable inherited heterozygous gain-of-function mutations in CXCR4 affecting homologous desensitization of the receptor, thus resulting in enhanced signaling following CXCL12 stimulation, defective lymphoid differentiation of HSPCs and reduced blood leukocyte numbers47–50. Here, CXCR4 is linked to WHIM syndrome.