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Nature. 2018 Jan 25;553(7689):515-520. doi: 10.1038/nature25193. Epub 2018 Jan 17.

A Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies.

Author information

1
Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
2
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
3
Faculty of Biosciences, University of Heidelberg, 69120 Heidelberg, Germany.
4
Developmental Biology Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany.
5
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.
6
Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1A1, Canada.
7
Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5G 1A1, Canada.
8
Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
9
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
10
German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
11
Nationales Zentrum für Tumorerkrankungen (NCT), 69120 Heidelberg, Germany.
12
CNRS, UMR3738, 25 Rue du Dr Roux, 75015 Paris, France.
13
(Epi)genomics of Animal Development Unit, Developmental and Stem Cell Biology Department, Institut Pasteur, 75015 Paris, France.

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.

PMID:
29342133
DOI:
10.1038/nature25193
[Indexed for MEDLINE]

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