TY  - JOUR
AU  - Gozdecka, Malgorzata
AU  - Meduri, Eshwar
AU  - Mazan, Milena
AU  - Tzelepis, Konstantinos
AU  - Dudek, Monika
AU  - Knights, Andrew J
AU  - Pardo, Mercedes
AU  - Yu, Lu
AU  - Choudhary, Jyoti S
AU  - Metzakopian, Emmanouil
AU  - Iyer, Vivek
AU  - Yun, Haiyang
AU  - Park, Naomi
AU  - Varela, Ignacio
AU  - Bautista, Ruben
AU  - Collord, Grace
AU  - Dovey, Oliver
AU  - Garyfallos, Dimitrios A
AU  - De Braekeleer, Etienne
AU  - Kondo, Saki
AU  - Cooper, Jonathan
AU  - Göttgens, Berthold
AU  - Bullinger, Lars
AU  - Northcott, Paul A
AU  - Adams, David
AU  - Vassiliou, George S
AU  - Huntly, Brian J P
TI  - UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs.
JO  - Nature genetics
VL  - 50
IS  - 6
SN  - 1546-1718
CY  - New York, NY
PB  - Nature America
M1  - DKFZ-2018-00693
SP  - 883 - 894
PY  - 2018
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:29736013
DO  - DOI:10.1038/s41588-018-0114-z
UR  - https://inrepo02.dkfz.de/record/135956
ER  -