@article{dc340918d33c47db855c8b67619b1868,
title = "A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia",
abstract = "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.",
author = "Voit, {Richard A.} and Liming Tao and Fulong Yu and Cato, {Liam D.} and Blake Cohen and Fleming, {Travis J.} and Mateusz Antoszewski and Xiaotian Liao and Claudia Fiorini and Nandakumar, {Satish K.} and Lara Wahlster and Kristian Teichert and Aviv Regev and Sankaran, {Vijay G.}",
note = "Funding Information: We are grateful to members of the Sankaran laboratory and numerous colleagues for valuable comments and suggestions. This work was supported by the New York Stem Cell Foundation (V.G.S.), a gift from the Lodish Family to Boston Children{\textquoteright}s Hospital (V.G.S.), the Klarman Cell Observatory (A.R.), the Edward P. Evans Foundation (V.G.S.) and National Institutes of Health Grants R01 DK103794, R01 CA265726 and R01 HL146500 (V.G.S.). R.A.V. and L.W. received support from National Institutes of Health Grant T32 HL007574. R.A.V. is supported by the Edward P. Evans Center for Myelodysplastic Syndromes at the Dana-Farber Cancer Institute, the Julia{\textquoteright}s Wings Foundation and the Office of Faculty Development at Boston Children{\textquoteright}s Hospital. S.K.N. is a Scholar of the American Society of Hematology. V.G.S. is a New York Stem Cell-Robertson Investigator. Funding Information: We are grateful to members of the Sankaran laboratory and numerous colleagues for valuable comments and suggestions. This work was supported by the New York Stem Cell Foundation (V.G.S.), a gift from the Lodish Family to Boston Children{\textquoteright}s Hospital (V.G.S.), the Klarman Cell Observatory (A.R.), the Edward P. Evans Foundation (V.G.S.) and National Institutes of Health Grants R01 DK103794, R01 CA265726 and R01 HL146500 (V.G.S.). R.A.V. and L.W. received support from National Institutes of Health Grant T32 HL007574. R.A.V. is supported by the Edward P. Evans Center for Myelodysplastic Syndromes at the Dana-Farber Cancer Institute, the Julia{\textquoteright}s Wings Foundation and the Office of Faculty Development at Boston Children{\textquoteright}s Hospital. S.K.N. is a Scholar of the American Society of Hematology. V.G.S. is a New York Stem Cell-Robertson Investigator. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2023",
month = jan,
doi = "10.1038/s41590-022-01370-4",
language = "English (US)",
volume = "24",
pages = "69--83",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "1",
}
