Clonal hematopoiesis of indeterminate potential and its impact on patient trajectories after stem cell transplantation

Clonal hematopoiesis of indeterminate potential (CHIP) is a recently identified process where older patients accumulate distinct subclones defined by recurring somatic mutations in hematopoietic stem cells. CHIP's implications for stem cell transplantation have been harder to identify due to the high degree of mutational heterogeneity that is present within the genetically distinct subclones. In order to gain a better understanding of CHIP and the impact of clonal dynamics on transplantation outcomes, we created a mathematical model of clonal competition dynamics. Our analyses highlight the importance of understanding competition intensity between healthy and mutant clones. Importantly, we highlight the risk that CHIP poses in leading to dominance of precancerous mutant clones and the risk of donor derived leukemia. Furthermore, we estimate the degree of competition intensity and bone marrow niche decline in mice during aging by using our modeling framework. Together, our work highlights the importance of better characterizing the ecological and clonal composition in hematopoietic donor populations at the time of stem cell transplantation. Author summary We investigated the impact of clonal hematopoiesis of indeterminate potential on stem cell transplantation outcomes. Interclonal competition intensity was identified as an important determinant of ultimate hematopoietic trajectory. We also investigated the impact of age-related marrow changes and show that, from a mouse model, these ecological parameters can be estimated.