Paper

A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia

Zhu, Qian, Herbert, Zachary T, Harada, Taku, Kalfon, Jeremie, Orkin, Stuart H, Li, Charles H, Ewers, Jazmin, Pimkin, Maxim, Eagle, Kenneth, Kugener, Guillaume, Stegmaier, Kimberly, Perez, Monika, Koren, Jost Vrabic, Dharia, Neekesh V, Wickramasinghe, Jayamanna, Lin, Charles Y, Dempster, Joshua M, Ferrucio, Juliana Xavier, Weinstock, David M, Paralkar, Vikram R, Yi, Joanna S, Ellegast, Jana M, Nabet, Behnam, Heshmati, Yaser, Bowker, Allyson, Kossenkov, Andrew

2021

Overview

A small set of lineage-restricted transcription factors (TFs), termed core regulatory circuitry (CRC), control cell identity and malignant transformation. Here, we integrated gene dependency, chromatin architecture and TF perturbation datasets to characterize 31 core TFs in acute myeloid leukemia (AML). Contrary to a widely accepted model, we detected a modular CRC structure with hierarchically organized, partially redundant and only sparsely interconnected modules of core TFs controlling distinct genetic programs. Rapid TF degradation followed by measurement of genome-wide transcription rates revealed that core TFs directly regulate dramatically fewer genes than previously assumed. Leukemias carrying KMT2A (MLL) rearrangements depend on the IRF8/MEF2 axis to directly enforce expression of the key oncogenes MYC, HOXA9 and BCL2. Our datasets provide an evolving model of CRC organization in human cells, and a resource for further inquiries into and therapeutic targeting of aberrant transcriptional circuits in cancer. Competing Interest Statement K. Stegmaier has funding from Novartis Institute of Biomedical Research, consults for and has stock options in Auron Therapeutics, and has consulted for Kronos Bio and AstraZeneca on topics unrelated to this work. N.V. Dharia is a current employee of Genentech, Inc., a member of the Roche Group. J. Xavier Ferrucio is a current employee of Vor Biopharma. C.Y. Lin is a current employee of Kronos Bio. B. Nabet is an inventor on patent applications related to the dTAG system (WO/2017/024318, WO/2017/024319, WO/2018/148440, WO/2018/148443 and WO/2020/146250). K. Eagle has consulted for Third Rock Ventures and Flare Therapeutics on topics unrelated to this manuscript. All other authors declare no potential conflict of interest.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Acute myeloid leukemia / Biotechnology / Chromatin / Genetic transformation / Genomes / Genomics / Leukemia / Medical research / Myc protein / Myeloid leukemia / Myocyte enhancer factor 2 / Oncogenes / Patent applications / Pharmacology / Therapeutic targets / Transcription factors