Genome-wide association study on 13 167 individuals identifies regulators of blood CD34+cell levels
(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.
(Less)
- author
- organization
-
- Division of Hematology and Transfusion Medicine
- Hematogenomics (research group)
- LUCC: Lund University Cancer Centre
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Stem Cell Center
- Division of Molecular Medicine and Gene Therapy
- Division of Molecular Hematology (DMH)
- Stem Cells and Leukemia (research group)
- MultiPark: Multidisciplinary research focused on Parkinson´s disease
- Department of Laboratory Medicine
- WCMM-Wallenberg Centre for Molecular Medicine
- publishing date
- 2022-03-17
- 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
- 2024-09-19 23:05:39
@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}}, }