The transcription factor Myc is essential for the regulation of haematopoietic stem cells and progenitors and has a critical function in haematopoietic malignancies1. 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’2 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 cells3. 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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We thank members of the Spitz and Trumpp laboratories and colleagues for sharing reagents and helpful comments; A. Przybylla, M. Sohn and M. Neubauer for technical assistance; L. Alfaro and W. Zhang for sample preparation for RNA sequencing; M. Milsom for critical reading of the manuscript; R. Grosschedl and S. Boller for help with B cell development analysis; and the DKFZ Flow Cytometry Core facility and the EMBL and DKFZ Laboratory Animal Resource Facilities. Support was provided by PhD fellowships to V.V.U. (Jeff Schell Darwin Trust); M.P. (EMBL international PhD program), C.B. (Helmholtz International Graduate School for Cancer Research) and post-doctoral fellowship to S.R. (EMBL (EIPOD) under Marie Curie Actions COFUND). The J.E.D. and M.L. laboratories were supported in part by the Medicine by Design program (Toronto University), the Ontario Institute for Cancer Research, Cancer Stem Cell Consortium (OGI-047), the Canadian Institutes of Health Research and the CIHR-Japan Epigenetics in Stem Cells Program, Canadian Cancer Society, Terry Fox Foundation, and a Canada Research Chair to J.E.D. The A.T. laboratory was supported by the SFB 873 and FOR 2674 (Deutsche Forschungsgemeinschaft), the SyTASC consortium (Deutsche Krebshilfe) and the Dietmar Hopp Foundation.