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Nat Genet. 2018 Jun;50(6):883-894. doi: 10.1038/s41588-018-0114-z. Epub 2018 May 7.

UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs.

Author information

1
Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
2
Wellcome Trust-MRC Stem Cell Institute, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
3
Genomics of Gene Regulation, Wellcome Trust Sanger Institute, Hinxton, UK.
4
Proteomic Mass Spectrometry, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
5
Mouse Genomics, Wellcome Trust Sanger Institute, Hinxton, UK.
6
Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
7
Sequencing Research Group, Wellcome Trust Sanger Institute, Cambridge, UK.
8
Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC-Sodercan), Departamento de Biología Molecular, Universidad de Cantabria, Santander, Spain.
9
New Pipeline Group, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
10
Laboratory of Molecular Genetics, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
11
Cambridge Institute for Medical Research and Wellcome Trust-Medical Research Council, Stem Cell Institute and Department of Haematology, University of Cambridge, Cambridge, UK.
12
Department of Internal Medicine III, Ulm University Medical Centre, Ulm, Germany.
13
Medical Department, Division of Hematology, Oncology and Tumour Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany.
14
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
15
Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
16
Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK. gsv20@sanger.ac.uk.
17
Wellcome Trust-MRC Stem Cell Institute, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK. gsv20@sanger.ac.uk.
18
Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge, UK. gsv20@sanger.ac.uk.
19
Wellcome Trust-MRC Stem Cell Institute, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK. bjph2@cam.ac.uk.
20
Cambridge Institute for Medical Research and Wellcome Trust-Medical Research Council, Stem Cell Institute and Department of Haematology, University of Cambridge, Cambridge, UK. bjph2@cam.ac.uk.
21
Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge, UK. bjph2@cam.ac.uk.

Abstract

The histone H3 Lys27-specific demethylase UTX (or KDM6A) is targeted by loss-of-function mutations in multiple cancers. Here, we demonstrate that UTX suppresses myeloid leukemogenesis through noncatalytic functions, a property shared with its catalytically inactive Y-chromosome paralog, UTY (or KDM6C). In keeping with this, we demonstrate concomitant loss/mutation of KDM6A (UTX) and UTY in multiple human cancers. Mechanistically, global genomic profiling showed only minor changes in H3K27me3 but significant and bidirectional alterations in H3K27ac and chromatin accessibility; a predominant loss of H3K4me1 modifications; alterations in ETS and GATA-factor binding; and altered gene expression after Utx loss. By integrating proteomic and genomic analyses, we link these changes to UTX regulation of ATP-dependent chromatin remodeling, coordination of the COMPASS complex and enhanced pioneering activity of ETS factors during evolution to AML. Collectively, our findings identify a dual role for UTX in suppressing acute myeloid leukemia via repression of oncogenic ETS and upregulation of tumor-suppressive GATA programs.

PMID:
29736013
PMCID:
PMC6029661
DOI:
10.1038/s41588-018-0114-z
[Indexed for MEDLINE]
Free PMC Article

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