A CADASIL-related NOTCH3 allele leads to haematopoietic stem and progenitor cells expansion and clonal haematopoiesis

The cellular and molecular mechanisms driving clonal haematopoietic (CH) selection, emergence, and evolution over the life of an individual are poorly understood. Previously, we identified the CADASIL-like C223Y mutation in the extracellular domain of NOTCH3 as a putative CH driver. This study aims to better understand the mechanisms that confer a selective advantage during CH and particularly, to explore if there is a plausible link between CADASIL and CH. In order to tacke these questions, we generated a mouse model expressing the CADASIL-associated NOTCH3 C455R mutation in all haematopoietic cells. We evaluated the impact of the expression of these mutations confering a selective proliferative advantage to haematopoietic and stem progenitor cells.