KBTBD4-UM171-CoREST1 Axis Prevents Stress-Induced Aging of Human Hematopoietic Stem Cells

UM171 is a small molecule degrader of CoREST1 and MYC through KBTBD4 E3 ligase activation. It was initially characterized as a potent hematopoietic stem cell (HSC) self-renewal agonist, with more recent evidence suggesting that it may counter aging-associated declines in HSC function. Here, using both scRNAseq and in vivo functional approaches, we provide evidence that several key features of HSC aging, notably reduction in lymphoid differentiation, serial transplantation competency, and quiescence, are modulated by UM171 dosage and subsequent CoREST1 degradation, gradually reaching maximal efficacy at a higher dose of 125nM. In such conditions, lymphoid output per HSC is markedly enhanced and provides robust hematopoiesis even in a stressful environment. Mechanistically, we identify several HSC clusters progressively affected by CoREST1 depletion, the most primitive one reaching peak expression of genes known to distinguish HSCs with superior engraftment potential, such as LMNA, RGCC, VIM, and ID at maximal CoREST1 degradation. Together, these data provide evidence for a rheostat function of the KBTBD4-UM171-CoREST1 axis in regulating HSC aging, counteracting the negative impact of stress.