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A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia
The molecular regulation of human hematopoietic stem cell (HSC) maintenance is therapeutically important, but limitations in experimental systems and interspecies variation have constrained our knowledge of this process. Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency,...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group US
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9810535/ https://www.ncbi.nlm.nih.gov/pubmed/36522544 http://dx.doi.org/10.1038/s41590-022-01370-4 |
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author | Voit, Richard A. Tao, Liming Yu, Fulong Cato, Liam D. Cohen, Blake Fleming, Travis J. Antoszewski, Mateusz Liao, Xiaotian Fiorini, Claudia Nandakumar, Satish K. Wahlster, Lara Teichert, Kristian Regev, Aviv Sankaran, Vijay G. |
author_facet | Voit, Richard A. Tao, Liming Yu, Fulong Cato, Liam D. Cohen, Blake Fleming, Travis J. Antoszewski, Mateusz Liao, Xiaotian Fiorini, Claudia Nandakumar, Satish K. Wahlster, Lara Teichert, Kristian Regev, Aviv Sankaran, Vijay G. |
author_sort | Voit, Richard A. |
collection | PubMed |
description | The molecular regulation of human hematopoietic stem cell (HSC) maintenance is therapeutically important, but limitations in experimental systems and interspecies variation have constrained our knowledge of this process. Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo. By generating a faithful model of this disorder in primary human HSCs and coupling functional studies with integrative single-cell genomic analyses, we uncover a key transcriptional network involving hundreds of genes that is required for HSC maintenance. Through our analyses, we nominate cooperating transcriptional regulators and identify how MECOM prevents the CTCF-dependent genome reorganization that occurs as HSCs differentiate. We show that this transcriptional network is co-opted in high-risk leukemias, thereby enabling these cancers to acquire stem cell properties. Collectively, we illuminate a regulatory network necessary for HSC self-renewal through the study of a rare experiment of nature. |
format | Online Article Text |
id | pubmed-9810535 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
spelling | pubmed-98105352023-01-05 A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia Voit, Richard A. Tao, Liming Yu, Fulong Cato, Liam D. Cohen, Blake Fleming, Travis J. Antoszewski, Mateusz Liao, Xiaotian Fiorini, Claudia Nandakumar, Satish K. Wahlster, Lara Teichert, Kristian Regev, Aviv Sankaran, Vijay G. Nat Immunol Article The molecular regulation of human hematopoietic stem cell (HSC) maintenance is therapeutically important, but limitations in experimental systems and interspecies variation have constrained our knowledge of this process. Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo. By generating a faithful model of this disorder in primary human HSCs and coupling functional studies with integrative single-cell genomic analyses, we uncover a key transcriptional network involving hundreds of genes that is required for HSC maintenance. Through our analyses, we nominate cooperating transcriptional regulators and identify how MECOM prevents the CTCF-dependent genome reorganization that occurs as HSCs differentiate. We show that this transcriptional network is co-opted in high-risk leukemias, thereby enabling these cancers to acquire stem cell properties. Collectively, we illuminate a regulatory network necessary for HSC self-renewal through the study of a rare experiment of nature. Nature Publishing Group US 2022-12-15 2023 /pmc/articles/PMC9810535/ /pubmed/36522544 http://dx.doi.org/10.1038/s41590-022-01370-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Voit, Richard A. Tao, Liming Yu, Fulong Cato, Liam D. Cohen, Blake Fleming, Travis J. Antoszewski, Mateusz Liao, Xiaotian Fiorini, Claudia Nandakumar, Satish K. Wahlster, Lara Teichert, Kristian Regev, Aviv Sankaran, Vijay G. A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia |
title | A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia |
title_full | A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia |
title_fullStr | A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia |
title_full_unstemmed | A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia |
title_short | A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia |
title_sort | genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9810535/ https://www.ncbi.nlm.nih.gov/pubmed/36522544 http://dx.doi.org/10.1038/s41590-022-01370-4 |
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