2. Academic Validation
  3. Heterochromatin fidelity is a therapeutic vulnerability in lymphoma and other human cancers

Heterochromatin fidelity is a therapeutic vulnerability in lymphoma and other human cancers

  • bioRxiv. 2025 Feb 5:2025.01.31.635709. doi: 10.1101/2025.01.31.635709.
Mohamad Ali Najia 1 2 3 4 5,  Deepak K Jha 3 4 5,  Cheng Zhang 6,  Benoit Laurent 7,  Caroline Kubaczka 3 4 5,  Arianna Markel 3 4 5,  Christopher Li 3 4 5,  Vivian Morris 3 4 5,  Allison Tompkins 3 4 5,  Luca Hensch 3 4 5,  Yue Qin 2,  Bjoern Chapuy 8 9,  Yu-Chung Huang 3 4 5,  Michael Morse 3 4 5,  Matthew R Marunde 10,  Anup Vaidya 10,  Zachary B Gillespie 10,  Sarah A Howard 10,  Trista E North 3 4 5 11,  Daniel Dominguez 12 13,  Michael-Christopher Keogh 10,  Thorsten M Schlaeger 3 4 5,  Yang Shi 7 14,  Hu Li 6,  Margaret M Shipp 8,  Paul C Blainey 2 15 16,  George Q Daley 3 4 5 11 17
Affiliations

Affiliations

  • 1 Harvard-MIT Division of Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 2 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 3 Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA.
  • 4 Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA.
  • 5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115 USA.
  • 6 Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic College of Medicine and Science, Rochester, MN, 55902, USA.
  • 7 Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston, MA, 02115, USA.
  • 8 Division of Hematologic Neoplasia, Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA.
  • 9 Charité, University Medical Center Berlin, Campus Benjamin Franklin, Berlin, Germany.
  • 10 EpiCypher Inc., Durham, NC 27709, USA.
  • 11 Developmental and Regenerative Biology Program, Harvard Medical School, Boston, MA 02115, USA.
  • 12 Department of Pharmacology, University of North Carolina, Chapel Hill, NC, 27599, USA.
  • 13 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 14 Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • 15 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 16 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 17 Lead contact.
PMID: 39975048 DOI: 10.1101/2025.01.31.635709
Abstract

Genes involved in the regulation of chromatin structure are frequently disrupted in Cancer, contributing to an aberrant transcriptome and phenotypic plasticity. Yet, therapeutics targeting mutant forms of chromatin-modifying Enzymes have yielded only modest clinical utility, underscoring the difficulty of targeting the epigenomic underpinnings of aberrant gene regulatory networks. Here, we sought to identify novel epigenetic vulnerabilities in diffuse large B-cell lymphoma (DLBCL). Through phenotypic screens and biochemical analysis, we demonstrated that inhibition of the H3K9 demethylases KDM4A and KDM4C elicits potent, subtype-agnostic cytotoxicity by antagonizing transcriptional networks associated with B-cell identity and epigenetically rewiring heterochromatin. KDM4 demethylases associated with the KRAB zinc finger ZNF587, and their enzymatic inhibition led to DNA replication stress and DNA damage-einduced cGAS-STING activation. Broad surveys of transcriptional data from patients also revealed KDM4 family dysregulation in several other Cancer types. To explore this potential therapeutic avenue, we performed high-throughput small molecule screens with H3K9me3 nucleosome substrates and identified novel KDM4 demethylase inhibitors. AI-guided protein-ligand binding predictions suggested diverse modes of action for various small molecule hits. Our findings underscore the relevance of targeting fundamental transcriptional and epigenetic mechanisms for anti-cancer therapy.

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