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Identification of regulators of hematopoietic stem and progenitor cells in vivo in humans using population genetics

Lopez de Lapuente Portilla, Aitzkoa LU ; Ekdahl, Ludvig LU ; Cafaro, Caterina LU ; Ali, Zain LU ; Ugidos Damboriena, Nerea LU ; Zemaitis, Kristijonas LU ; Larsson, Jonas LU and Nilsson, Björn LU (2020) European Human Genetics Virtual Conference
Abstract
Introduction: Understanding how hematopoietic stem- and progenitor cells (HSPCs) are regulated is of central importance for the development of new therapies for blood disorders and for regenerative medicine. Traditionally, however, HSPC regulation has been studied in model systems, and little is known about the situation in vivo in humans. Methods: To learn how HSPCs are regulated under native conditions in humans, we carried out a first large-scale genome-wide association study on CD34+ cells, representing HSPCs in blood. We used circulating CD34+ levels as a proxy trait to expose regulators of key phenomena like HSPC pool size, migration, and early differentiation. We created a unique phenotyping platform based on high-throughput,... (More)
Introduction: Understanding how hematopoietic stem- and progenitor cells (HSPCs) are regulated is of central importance for the development of new therapies for blood disorders and for regenerative medicine. Traditionally, however, HSPC regulation has been studied in model systems, and little is known about the situation in vivo in humans. Methods: To learn how HSPCs are regulated under native conditions in humans, we carried out a first large-scale genome-wide association study on CD34+ cells, representing HSPCs in blood. We used circulating CD34+ levels as a proxy trait to expose regulators of key phenomena like HSPC pool size, migration, and early differentiation. We created a unique phenotyping platform based on high-throughput, high-resolution flow-cytometry and machine learning-based algorithms for automated flow data analysis, and quantified CD34+ cells in 9,936 adults.Results: We identified 8 genome-wide (P<5x10-8) and 20 suggestive loci (P<5x10-6) associated with CD34+ levels. The two strongest were the HSPC migration receptor CXCR4 and a novel protein phosphatase never previously implicated in stem cell biology. Using eQTL, ATAC-seq, and promoter capture Hi-C analysis in isolated HSPCs, we pinpoint likely causal variants, including variants in distant regulatory elements selectively active in specific HSPC subpopulations. Furthermore, shRNA knockdown in primary CD34+ cells supports that some of the identified genes affect CD34+ proliferation and differentiation.Conclusions: We report the first large-scale analysis of the genetic architecture of HSPC regulation, with potential implications for stem cell transplantation and the treatment of hematologic malignancies.Grant information: European Research Council, Swedish Research Council, Swedish Cancer Society. (Less)
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Contribution to conference
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conference name
European Human Genetics Virtual Conference
conference dates
2020-06-06 - 2020-06-08
language
English
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yes
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4bcbf8d9-a631-4183-a3bd-1cba4fd96816
date added to LUP
2021-01-17 18:51:17
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2021-04-26 09:40:02
@misc{4bcbf8d9-a631-4183-a3bd-1cba4fd96816,
  abstract     = {{Introduction: Understanding how hematopoietic stem- and progenitor cells (HSPCs) are regulated is of central importance for the development of new therapies for blood disorders and for regenerative medicine. Traditionally, however, HSPC regulation has been studied in model systems, and little is known about the situation in vivo in humans. Methods: To learn how HSPCs are regulated under native conditions in humans, we carried out a first large-scale genome-wide association study on CD34+ cells, representing HSPCs in blood. We used circulating CD34+ levels as a proxy trait to expose regulators of key phenomena like HSPC pool size, migration, and early differentiation. We created a unique phenotyping platform based on high-throughput, high-resolution flow-cytometry and machine learning-based algorithms for automated flow data analysis, and quantified CD34+ cells in 9,936 adults.Results: We identified 8 genome-wide (P&lt;5x10-8) and 20 suggestive loci (P&lt;5x10-6) associated with CD34+ levels. The two strongest were the HSPC migration receptor CXCR4 and a novel protein phosphatase never previously implicated in stem cell biology. Using eQTL, ATAC-seq, and promoter capture Hi-C analysis in isolated HSPCs, we pinpoint likely causal variants, including variants in distant regulatory elements selectively active in specific HSPC subpopulations. Furthermore, shRNA knockdown in primary CD34+ cells supports that some of the identified genes affect CD34+ proliferation and differentiation.Conclusions: We report the first large-scale analysis of the genetic architecture of HSPC regulation, with potential implications for stem cell transplantation and the treatment of hematologic malignancies.Grant information: European Research Council, Swedish Research Council, Swedish Cancer Society.}},
  author       = {{Lopez de Lapuente Portilla, Aitzkoa and Ekdahl, Ludvig and Cafaro, Caterina and Ali, Zain and Ugidos Damboriena, Nerea and Zemaitis, Kristijonas and Larsson, Jonas and Nilsson, Björn}},
  language     = {{eng}},
  month        = {{06}},
  title        = {{Identification of regulators of hematopoietic stem and progenitor cells in vivo in humans using population genetics}},
  year         = {{2020}},
}