Genome-wide association study on 13 167 individuals identifies regulators of blood CD34+cell levels.

Stem cell transplantation is a cornerstone in the treatment of blood malignancies. The most common method to harvest stem cells for transplantation is by leukapheresis, requiring mobilization of CD34+ hematopoietic stem and progenitor cells (HSPCs) from the bone marrow into the blood. Identifying the genetic factors that control blood CD34+ cell levels could reveal new drug targets for HSPC mobilization. Here we report the first large-scale, genome-wide association study on blood CD34+ cell levels. Across 13 167 individuals, we identify 9 significant and 2 suggestive associations, accounted for by 8 loci (PPM1H, CXCR4, ENO1-RERE, ITGA9, ARHGAP45, CEBPA, TERT, and MYC). Notably, 4 of the identified associations map to CXCR4, showing that bona fide regulators of blood CD34+ cell levels can be identified through genetic variation. Further, the most significant association maps to PPM1H, encoding a serine/threonine phosphatase never previously implicated in HSPC biology. PPM1H is expressed in HSPCs, and the allele that confers higher blood CD34+ cell levels downregulates PPM1H. Through functional fine-mapping, we find that this downregulation is caused by the variant rs772557-A, which abrogates an MYB transcription factor-binding site in PPM1H intron 1 that is active in specific HSPC subpopulations, including hematopoietic stem cells, and interacts with the promoter by chromatin looping. Furthermore, PPM1H knockdown increases the proportion of CD34+ and CD34+90+ cells in cord blood assays. Our results provide the first large-scale analysis of the genetic architecture of blood CD34+ cell levels and warrant further investigation of PPM1H as a potential inhibition target for stem cell mobilization. © 2022 by The American Society of Hematology.

Citation

Aitzkoa Lopez de Lapuente Portilla, Ludvig Ekdahl, Caterina Cafaro, Zain Ali, Natsumi Miharada, Gudmar Thorleifsson, Kristijonas Žemaitis, Antton Lamarca Arrizabalaga, Malte Thodberg, Maroulio Pertesi, Parashar Dhapola, Erik Bao, Abhishek Niroula, Divya Bali, Gudmundur Norddahl, Nerea Ugidos Damboriena, Vijay G Sankaran, Göran Karlsson, Unnur Thorsteinsdottir, Jonas Larsson, Kari Stefansson, Björn Nilsson. Genome-wide association study on 13 167 individuals identifies regulators of blood CD34+cell levels. Blood. 2022 Mar 17;139(11):1659-1669

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PMID: 35007327

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