A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia

• Published in: Nature immunology Vol. 24; no. 1; pp. 69 - 83
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2023; Nature Publishing Group
• Subjects: 631/250/232; 631/250/2502; 631/532/1542; 692/699/249/2512; 692/699/67/1990/283; Age; Biomedical and Life Sciences; Biomedicine; Bone marrow; Cell Differentiation - genetics; Cell self-renewal; Genetic disorders; Genomic analysis; Haploinsufficiency; Hematopoietic Stem Cells; Humans; Immunology; Infectious Diseases; Leukemia; Leukemia - genetics; Neoplasms; Stem cells; Transcription Factors - genetics
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-022-01370-4

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. Modeling a rare bone marrow failure disorder due to haploinsufficiency for the MECOM transcription factor identifies a human hematopoietic stem cell regulatory network, which is co-opted by high-risk leukemias.