Journal
NATURE GENETICS
Volume 50, Issue 6, Pages 883-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41588-018-0114-z
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Funding
- Bloodwise Program [17006]
- ERC consolidator award [647685 COMAL]
- Cancer Research UK program award
- Medical Research Council, (MRC)
- Wellcome Trust (WT)
- Cambridge NIHR BRC
- WT/MRC Center grant [097922/Z/11/Z]
- WT strategic award [100140]
- Cancer Research UK Senior Cancer Research Fellowship [C22324/A23015]
- Kay Kendall Leukemia Fund
- Sanger Institute [WT098051]
- Wellcome Trust [097922/Z/11/Z] Funding Source: Wellcome Trust
- MRC [MR/M010392/1, MR/R009708/1] Funding Source: UKRI
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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.
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