A Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies
Abstract
The transcription factor Myc is essential for the regulation of haematopoietic stem cells and progenitors and has a critical function in haematopoietic malignancies. Here we show that an evolutionarily conserved region located 1.7 megabases downstream of the Myc gene that has previously been labelled as a 'super-enhancer' is essential for the regulation of Myc expression levels in both normal haematopoietic and leukaemic stem cell hierarchies in mice and humans. Deletion of this region in mice leads to a complete loss of Myc expression in haematopoietic stem cells and progenitors. This caused an accumulation of differentiation-arrested multipotent progenitors and loss of myeloid and B cells, mimicking the phenotype caused by Mx1-Cre-mediated conditional deletion of the Myc gene in haematopoietic stem cells. This super-enhancer comprises multiple enhancer modules with selective activity that recruits a compendium of transcription factors, including GFI1b, RUNX1 and MYB. Analysis of mice carrying deletions of individual enhancer modules suggests that specific Myc expression levels throughout most of the haematopoietic hierarchy are controlled by the combinatorial and additive activity of individual enhancer modules, which collectively function as a 'blood enhancer cluster' (BENC). We show that BENC is also essential for the maintenance of MLL-AF9-driven leukaemia in mice. Furthermore, a BENC module, which controls Myc expression in mouse haematopoietic stem cells and progenitors, shows increased chromatin accessibility in human acute myeloid leukaemia stem cells compared to blasts. This difference correlates with MYC expression and patient outcome. We propose that clusters of enhancers, such as BENC, form highly combinatorial systems that allow precise control of gene expression across normal cellular hierarchies and which also can be hijacked in malignancies.
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Combinatorial occupancy of chromatin by multiple master transcription factors has revealed key regulatory elements necessary for HSC self-renewal.
“For instance, the combinatorial occupancy of chromatin by multiple master TFs has revealed regulatory networks that are important for hematopoiesis (Beck et al., 2013; Schütte et al., 2016), as well as key regulatory elements necessary for HSC self-renewal (Bahr et al., 2018).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Bahr et al., 2018
Even studies at a single locus can be illuminating, as exemplified by the identification of a hematopoietic-specific enhancer of MYC that is required by HSCs.
“Even studies at a single locus can be illuminating, as exemplified by the identification of a hematopoietic-specific enhancer of MYC that is required by HSCs (Bahr et al., 2018) (Figure 4B).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Bahr et al., 2018
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- Authors
- Bahr, C., von Paleske, L., Uslu, V. V., Remeseiro, S., Takayama, N., Ng, S. W., Murison, A., Langenfeld, K., Petretich, M., Scognamiglio, R., Zeisberger, P., Benk, A. S., Amit, I., Zandstra, P. W., Lupien, M., Dick, J. E., Trumpp, A., & Spitz, F.
- Affiliations
- German Cancer Research Center (DE)
- European Molecular Biology Laboratory (DE)
- University Health Network (CA)
- University of Toronto (CA)
- Weizmann Institute of Science (IL)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Trumpp, Andreas
- Spitz, François
- ORCID
- Venue
- Nature
- Published
- 2018-01-17
- Volume
- 553
- Issue
- 7689
- Pages
- 515-520
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2783692764
- Cited by
- 328
- References
- 49
- Citations by year
- 2026: 16 · 2025: 30 · 2024: 35 · 2023: 60 · 2022: 38 · 2021: 53 · 2020: 43 · 2019: 29 · 2018: 23
- FWCI
- 13.34
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-05-16)
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Deutsches Krebsforschungszentrum
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- c-Myc, super-enhancers, enhancer clusters, hematopoietic stem cells, hematopoietic progenitor cells, leukemia stem cells, acute myeloid leukemia, GFI1B, RUNX1, MYB, chromatin accessibility, transcriptional regulation
- MeSH terms
- Animals, B-Lymphocytes, Cell Differentiation, Chromatin, Enhancer Elements, Genetic, Female, Gene Expression Regulation, Multigene Family, Hematopoietic Stem Cells, Humans, Leukemia, Male, Mice, Inbred C57BL, Prognosis, Transcription Factors, Neoplastic Stem Cells, Leukemia, Myeloid, Acute, Down-Regulation, Survival Analysis, Genes, myc, Gene Deletion, Sequence Deletion, Cell Lineage, Myeloid Cells, Multipotent Stem Cells, Mice
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