Stem cell transplantation is an essential component of the therapy of blood cancers. The most popular approach for harvesting stem cells for transplantation is leukapheresis, which involves mobilizing CD34+ hematopoietic stem and progenitor cells (HSPCs) from the bone marrow into the blood. Identifying the genetic mechanisms that regulate blood CD34+ cell numbers might lead to the identification of novel therapeutic targets for HSPC mobilization. The first large-scale genome-wide association analysis on blood CD34+ cell counts is presented here. For a study, researchers found 9 significant and 2 suggestive relationships among 13,167 people, with 8 loci accounting for them (PPM1H, CXCR4, ENO1-RERE, ITGA9, ARHGAP45, CEBPA, TERT, and MYC). Notably, 4 of the discovered relationships map to CXCR4, indicating that true controllers of blood CD34+ cell levels might be found via genetic variation.
Furthermore, the most important link was to PPM1H, which encodes a serine/threonine phosphatase that had never been implicated in HSPC biology. PPM1H was expressed in HSPCs, and the genotype that gives increased blood CD34+ cell numbers suppresses PPM1H expression. Investigators discovered that the mutation rs772557-A caused this downregulation by removing an MYB transcription factor–binding site in PPM1H intron 1 that is active in particular HSPC subpopulations, including hematopoietic stem cells, and interacted with the promoter via chromatin looping. Additionally, in cord blood tests, PPM1H knockdown increased the fraction of CD34+ and CD34+90+ cells. The findings were the first large-scale examination of the genetic architecture of blood CD34+ cell levels, and they call for more research into PPM1H as a potential inhibitor target for stem cell mobilization.