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000135956 0247_ $$2doi$$a10.1038/s41588-018-0114-z
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000135956 0247_ $$2ISSN$$a1061-4036
000135956 0247_ $$2ISSN$$a1546-1718
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000135956 037__ $$aDKFZ-2018-00693
000135956 041__ $$aeng
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000135956 1001_ $$aGozdecka, Malgorzata$$b0
000135956 245__ $$aUTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs.
000135956 260__ $$aNew York, NY$$bNature America$$c2018
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000135956 520__ $$aThe histone H3 Lys27-specific demethylase UTX (or KDM6A) is targeted by loss-of-function mutations in multiple cancers. Here, we demonstrate that UTX suppresses myeloid leukemogenesis through noncatalytic functions, a property shared with its catalytically inactive Y-chromosome paralog, UTY (or KDM6C). In keeping with this, we demonstrate concomitant loss/mutation of KDM6A (UTX) and UTY in multiple human cancers. Mechanistically, global genomic profiling showed only minor changes in H3K27me3 but significant and bidirectional alterations in H3K27ac and chromatin accessibility; a predominant loss of H3K4me1 modifications; alterations in ETS and GATA-factor binding; and altered gene expression after Utx loss. By integrating proteomic and genomic analyses, we link these changes to UTX regulation of ATP-dependent chromatin remodeling, coordination of the COMPASS complex and enhanced pioneering activity of ETS factors during evolution to AML. Collectively, our findings identify a dual role for UTX in suppressing acute myeloid leukemia via repression of oncogenic ETS and upregulation of tumor-suppressive GATA programs.
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000135956 7001_ $$aMeduri, Eshwar$$b1
000135956 7001_ $$aMazan, Milena$$b2
000135956 7001_ $$00000-0002-4865-7648$$aTzelepis, Konstantinos$$b3
000135956 7001_ $$aDudek, Monika$$b4
000135956 7001_ $$aKnights, Andrew J$$b5
000135956 7001_ $$00000-0002-3477-9695$$aPardo, Mercedes$$b6
000135956 7001_ $$00000-0001-8378-9112$$aYu, Lu$$b7
000135956 7001_ $$aChoudhary, Jyoti S$$b8
000135956 7001_ $$aMetzakopian, Emmanouil$$b9
000135956 7001_ $$aIyer, Vivek$$b10
000135956 7001_ $$aYun, Haiyang$$b11
000135956 7001_ $$aPark, Naomi$$b12
000135956 7001_ $$00000-0002-0969-506X$$aVarela, Ignacio$$b13
000135956 7001_ $$aBautista, Ruben$$b14
000135956 7001_ $$00000-0003-1924-4411$$aCollord, Grace$$b15
000135956 7001_ $$aDovey, Oliver$$b16
000135956 7001_ $$aGaryfallos, Dimitrios A$$b17
000135956 7001_ $$aDe Braekeleer, Etienne$$b18
000135956 7001_ $$aKondo, Saki$$b19
000135956 7001_ $$aCooper, Jonathan$$b20
000135956 7001_ $$00000-0001-6302-5705$$aGöttgens, Berthold$$b21
000135956 7001_ $$aBullinger, Lars$$b22
000135956 7001_ $$0P:(DE-HGF)0$$aNorthcott, Paul A$$b23
000135956 7001_ $$aAdams, David$$b24
000135956 7001_ $$00000-0003-4337-8022$$aVassiliou, George S$$b25
000135956 7001_ $$00000-0003-0312-161X$$aHuntly, Brian J P$$b26
000135956 773__ $$0PERI:(DE-600)1494946-5$$a10.1038/s41588-018-0114-z$$gVol. 50, no. 6, p. 883 - 894$$n6$$p883 - 894$$tNature genetics$$v50$$x1546-1718$$y2018
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000135956 9141_ $$y2018
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