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

Lopez de Lapuente Portilla, Aitzkoa LU ; Ekdahl, Ludvig LU ; Cafaro, Caterina LU ; Ali, Zain LU ; Miharada, Natsumi LU ; Thorleifsson, Gudmar ; Žemaitis, Kristijonas ; Lamarca Arrizabalaga, Antton LU ; Thodberg, Malte LU and Pertesi, Maroulio LU , et al. (2022) In Blood 139(11). p.1659-1669
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
139
issue
11
pages
11 pages
publisher
American Society of Hematology
external identifiers
  • pmid:35007327
  • scopus:85126368720
ISSN
0006-4971
DOI
10.1182/blood.2021013220
language
English
LU publication?
yes
id
6f643baf-3ca3-4575-a087-36858223b719
date added to LUP
2022-06-08 12:20:19
date last changed
2024-06-13 13:53:48
@article{6f643baf-3ca3-4575-a087-36858223b719,
  abstract     = {{<p>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<sup>+</sup> hematopoietic stem and progenitor cells (HSPCs) from the bone marrow into the blood. Identifying the genetic factors that control blood CD34<sup>+</sup> cell levels could reveal new drug targets for HSPC mobilization. Here we report the first large-scale, genome-wide association study on blood CD34<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> and CD34<sup>+</sup>90<sup>+</sup> cells in cord blood assays. Our results provide the first large-scale analysis of the genetic architecture of blood CD34<sup>+</sup> cell levels and warrant further investigation of PPM1H as a potential inhibition target for stem cell mobilization.</p>}},
  author       = {{Lopez de Lapuente Portilla, Aitzkoa and Ekdahl, Ludvig and Cafaro, Caterina and Ali, Zain and Miharada, Natsumi and Thorleifsson, Gudmar and Žemaitis, Kristijonas and Lamarca Arrizabalaga, Antton and Thodberg, Malte and Pertesi, Maroulio and Dhapola, Parashar and Bao, Erik and Niroula, Abhishek and Bali, Divya and Norddahl, Gudmundur and Ugidos Damboriena, Nerea and Sankaran, Vijay G. and Karlsson, Göran and Thorsteinsdottir, Unnur and Larsson, Jonas and Stefansson, Kari and Nilsson, Björn}},
  issn         = {{0006-4971}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{11}},
  pages        = {{1659--1669}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood}},
  title        = {{Genome-wide association study on 13 167 individuals identifies regulators of blood CD34<sup>+</sup>cell levels}},
  url          = {{http://dx.doi.org/10.1182/blood.2021013220}},
  doi          = {{10.1182/blood.2021013220}},
  volume       = {{139}},
  year         = {{2022}},
}