|Seminars in Experimental Medicine||13:00-14:00|
|Haus 06 Frauenklinik (4.Stock), Hörsaal 434|
The CXCL12/CXCR4 signalling exerts a dominant role in promoting hematopoietic stem and progenitor cell retention and quiescence in bone marrow. Gain-of-function CXCR4 mutations that affect homologous desensitization of the receptor have been reported in the WHIM Syndrome, a rare immunodeficiency characterized by lymphopenia. The mechanisms underpinning this remain obscure. Using a mouse model with a naturally occurring WHIM Syndrome-linked gain-of-function Cxcr4 mutation, we showed that the lymphopenia in WHIM Syndrome arises from defects at the hematopoietic stem and progenitor cell level. We found that Cxcr4 desensitization is required for quiescence/cycling balance of murine short-term hematopoietic stem cells and their differentiation into multipotent and downstream lymphoid-biased progenitors. Alteration in Cxcr4 desensitization resulted in decrease of circulating hematopoietic stem and progenitor cells in five patients with WHIM Syndrome. In this seminar, I will discuss how Cxcr4 desensitization impacts lymphoid differentiation of hematopoietic stem and progenitor cells and outline potential mechanisms underpinning the lymphopenia observed in WHIM Syndrome patients.