The GNASR201C mutation associated with clonal hematopoiesis supports transplantable hematopoietic stem cell activity

•GNASR201C mutation supports transplantable hematopoietic stem cell (HSC) activity.•GNASR201C mutation sustains lymphoid differentiation potential of long-term HSCs.•GNASR201C mutations may contribute to clonal hematopoiesis of indeterminate potential, but not necessarily hematopoietic transformation. Genome sequencing efforts have identified virtually all of the important mutations in adult myeloid malignancies. More recently, population studies have identified cancer-associated variants in the blood of otherwise healthy individuals as they age, a phenomenon termed clonal hematopoiesis of indeterminate potential (CHIP). This suggests that these mutations may occur in hematopoietic stem cells (HSCs) long before any clinical presentation but are not necessarily harbingers of transformation because only a fraction of individuals with CHIP develop hematopoietic pathologies. Delineation between CHIP variants that predispose for disease versus those that are more benign could be used as a prognostic factor to identify individuals at greater risk for transformation. To achieve this, the biological impact of CHIP variants on HSC function must be validated. One variant that has been identified recurrently in CHIP is a gain-of-function missense mutation in the imprinted gene GNAS (Guanine Nucleotide Binding Protein, Alpha Stimulating). In this study, we examined the effect of the GNASR201C variant on HSC function. Ectopic expression of GNASR201C supported transplantable HSC activity and improved lymphoid output in secondary recipients. Because declining lymphoid output is a hallmark of aging, GNASR201C mutations may sustain lymphoid-biased HSCs over time and maintain them in a developmental state favorable for transformation.