%0 Journal Article
%A Gozdecka, Malgorzata
%A Meduri, Eshwar
%A Mazan, Milena
%A Tzelepis, Konstantinos
%A Dudek, Monika
%A Knights, Andrew J
%A Pardo, Mercedes
%A Yu, Lu
%A Choudhary, Jyoti S
%A Metzakopian, Emmanouil
%A Iyer, Vivek
%A Yun, Haiyang
%A Park, Naomi
%A Varela, Ignacio
%A Bautista, Ruben
%A Collord, Grace
%A Dovey, Oliver
%A Garyfallos, Dimitrios A
%A De Braekeleer, Etienne
%A Kondo, Saki
%A Cooper, Jonathan
%A Göttgens, Berthold
%A Bullinger, Lars
%A Northcott, Paul A
%A Adams, David
%A Vassiliou, George S
%A Huntly, Brian J P
%T UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs.
%J Nature genetics
%V 50
%N 6
%@ 1546-1718
%C New York, NY
%I Nature America
%M DKFZ-2018-00693
%P 883 - 894
%D 2018
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:29736013
%R 10.1038/s41588-018-0114-z
%U https://inrepo02.dkfz.de/record/135956