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@ARTICLE{Gozdecka:135956,
author = {M. Gozdecka and E. Meduri and M. Mazan and K. Tzelepis and
M. Dudek and A. J. Knights and M. Pardo and L. Yu and J. S.
Choudhary and E. Metzakopian and V. Iyer and H. Yun and N.
Park and I. Varela and R. Bautista and G. Collord and O.
Dovey and D. A. Garyfallos and E. De Braekeleer and S. Kondo
and J. Cooper and B. Göttgens and L. Bullinger and P. A.
Northcott$^*$ and D. Adams and G. S. Vassiliou and B. J. P.
Huntly},
title = {{UTX}-mediated enhancer and chromatin remodeling suppresses
myeloid leukemogenesis through noncatalytic inverse
regulation of {ETS} and {GATA} programs.},
journal = {Nature genetics},
volume = {50},
number = {6},
issn = {1546-1718},
address = {New York, NY},
publisher = {Nature America},
reportid = {DKFZ-2018-00693},
pages = {883 - 894},
year = {2018},
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.},
cin = {B062},
ddc = {570},
cid = {I:(DE-He78)B062-20160331},
pnm = {312 - Functional and structural genomics (POF3-312)},
pid = {G:(DE-HGF)POF3-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:29736013},
doi = {10.1038/s41588-018-0114-z},
url = {https://inrepo02.dkfz.de/record/135956},
}