Blood malignancies affect over 4000 people in Sweden every year. In many cases, stem cell transplantation is an important part of the treatment. The most common method to harvest stem cells for transplantation is by leukapheresis, a process where white blood cells enriched for HSPCs are separated from the rest of the blood. For this method to work, the blood needs to contain a sufficiently high concentration of HSPCs. Therefore, HSPCs need to be tricked into moving out, or “mobilized”, from the bone marrow into the donor’s blood prior to harvesting.
In their new study, the Nilsson lab sought to answer an old question of great clinical significance: What genetic determinants control the number of hematopoietic stem and progenitor cells in the blood stream of an individual? Identifying these factors could expose new drug targets for HSPC mobilization.
To answer this question, the lab carried out the first large-scale genome-wide association study (GWAS) on blood stem cells. Their study included 13,167 blood donors and primary care patients from Region Skåne aged 18 to 71 years. It revealed 9 significant and 2 suggestive associations, accounted for by 8 loci. Remarkably, 4 of these associations map to CXCR4, a well-known factor for HSPC mobilization that is already targeted in the clinic by the drug Plerixafor. This confirmed the lab’s hypothesis that true drug targets for stem mobilization can be identified in vivo in humans through GWAS.
The strongest finding, however, was a completely unexpected gene: PPM1H. This gene encodes a serine/threonine phosphatase never previously been implicated in stem cell biology. It is expressed in HSPCs. The genetic variant that increases blood HSPC levels downregulates PPM1H in HSPCs. The study therefore warrants further investigation of PPM1H as a new inhibition target for stem cell mobilization, potentially facilitating stem cell harvesting in the treatment of blood disorders.
Further reading:
The full-text article: “Genome-wide association study on 13,167 individuals identifies regulators of blood CD34+ cell levels” published in Blood.
The homepage of Björn Nilsson's research group.
