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Mutational synergy during leukemia induction remodels chromatin accessibility, histone modifications and three-dimensional DNA topology to alter gene expression
Nature Genetics  (IF38.33),  Pub Date : 2021-09-23, DOI: 10.1038/s41588-021-00925-9
Haiyang Yun, Nisha Narayan, Shabana Vohra, George Giotopoulos, Annalisa Mupo, Pedro Madrigal, Daniel Sasca, David Lara-Astiaso, Sarah J. Horton, Shuchi Agrawal-Singh, Eshwar Meduri, Faisal Basheer, Ludovica Marando, Malgorzata Gozdecka, Oliver M. Dovey, Aracely Castillo-Venzor, Xiaonan Wang, Paolo Gallipoli, Carsten Müller-Tidow, Cameron S. Osborne, George S. Vassiliou, Brian J. P. Huntly

Altered transcription is a cardinal feature of acute myeloid leukemia (AML); however, exactly how mutations synergize to remodel the epigenetic landscape and rewire three-dimensional DNA topology is unknown. Here, we apply an integrated genomic approach to a murine allelic series that models the two most common mutations in AML: Flt3-ITD and Npm1c. We then deconvolute the contribution of each mutation to alterations of the epigenetic landscape and genome organization, and infer how mutations synergize in the induction of AML. Our studies demonstrate that Flt3-ITD signals to chromatin to alter the epigenetic environment and synergizes with mutations in Npm1c to alter gene expression and drive leukemia induction. These analyses also allow the identification of long-range cis-regulatory circuits, including a previously unknown superenhancer of Hoxa locus, as well as larger and more detailed gene-regulatory networks, driven by transcription factors including PU.1 and IRF8, whose importance we demonstrate through perturbation of network members.