Malgorzata Gozdecka, Eshwar Meduri, Milena Mazan, Konstantinos Tzelepis, Monika Dudek, Andrew J. Knights, Mercedes Pardo, Lu Yu, Jyoti S. Choudhary, Emmanouil Metzakopian, Vivek Iyer, Haiyang Yun, Naomi Park, Ignacio Varela, Ruben Bautista, Grace Collord, Oliver Dovey, Dimitrios A. Garyfallos, Etienne De Braekeleer, Saki Kondo, Jonathan Cooper, Berthold Göttgens, Lars Bullinger, Paul A. Northcott, David Adams, George S. Vassiliou, Brian J. P. Huntly

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.