A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia
- Taku Harada1,12,
- Yaser Heshmati1,12,
- Jérémie Kalfon2,12,
- Monika W. Perez1,
- Juliana Xavier Ferrucio1,
- Jazmin Ewers1,
- Benjamin Hubbell Engler1,
- Andrew Kossenkov3,
- Jana M. Ellegast1,2,
- Joanna S. Yi4,
- Allyson Bowker1,
- Qian Zhu1,
- Kenneth Eagle1,5,
- Tianxin Liu1,
- Yan Kai1,
- Joshua M. Dempster2,
- Guillaume Kugener2,
- Jayamanna Wickramasinghe3,
- Zachary T. Herbert6,
- Charles H. Li7,8,
- Jošt Vrabič Koren4,
- David M. Weinstock6,
- Vikram R. Paralkar9,
- Behnam Nabet10,
- Charles Y. Lin4,
- Neekesh V. Dharia1,2,
- Kimberly Stegmaier1,2,
- Stuart H. Orkin1,11 and
- Maxim Pimkin1,2
- 1Cancer and Blood Disorders Center, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA;
- 2Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA;
- 3The Wistar Institute, Philadelphia, Pennsylvania 19104, USA;
- 4Baylor College of Medicine, Houston, Texas 77030, USA;
- 5Ken Eagle Consulting, Houston, Texas 77494, USA;
- 6Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA;
- 7Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA;
- 8Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA;
- 9Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 10Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
- 11Howard Hughes Medical Institute, Boston, Massachusetts 02215, USA
- Corresponding authors: stuart_orkin{at}dfci.harvard.edu, maxim_pimkin{at}dfci.harvard.edu
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↵12 These authors contributed equally and are listed alphabetically
Abstract
Acute myeloid leukemia with KMT2A (MLL) rearrangements is characterized by specific patterns of gene expression and enhancer architecture, implying unique core transcriptional regulatory circuitry. Here, we identified the transcription factors MEF2D and IRF8 as selective transcriptional dependencies of KMT2A-rearranged AML, where MEF2D displays partially redundant functions with its paralog, MEF2C. Rapid transcription factor degradation followed by measurements of genome-wide transcription rates and superresolution microscopy revealed that MEF2D and IRF8 form a distinct core regulatory module with a narrow direct transcriptional program that includes activation of the key oncogenes MYC, HOXA9, and BCL2. Our study illustrates a mechanism of context-specific transcriptional addiction whereby a specific AML subclass depends on a highly specialized core regulatory module to directly enforce expression of common leukemia oncogenes.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.349284.121.
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Freely available online through the Genes & Development Open Access option.
- Received December 8, 2021.
- Accepted February 22, 2022.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
