ArticleCell2023
Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement.
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Article in Cell, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14citing papers in PubMed
5.2field-weighted citation impact, top 4% of its field
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Who cites it
14 citing papers in PubMed, 18 citations in OpenAlex.
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- Epigenetic priming promotes tyrosine kinase inhibitor resistance and oncogene amplification.Nature structural & molecular biology · 2026Article
- Uncovering chromatin factor landscapes in head and neck squamous cell carcinoma.Oral oncology · 2025Article
- KMT2A facilitates the epithelial-to-mesenchymal transition and the progression of ovarian cancer.Molecular and cellular biochemistry · 2025Article
- Review
- Current advances and future directions in targeting histone demethylases for cancer therapy.Molecules and cells · 2025Review
- HTAD: a human-in-the-loop framework for supervised chromatin domain detection.Genome biology · 2024Article
- Versatile JMJD proteins: juggling histones and much more.Trends in biochemical sciences · 2024Review
- Epigenetic modulators provide a path to understanding disease and therapeutic opportunity.Genes & development · 2024Review
- Aging and comprehensive molecular profiling in acute myeloid leukemia.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Thinking outside the chromosome: epigenetic mechanisms in non-canonical chromatin species.Nature structural & molecular biology · 2024Article
- The role of epigenetics in women's reproductive health: the impact of environmental factors.Frontiers in endocrinology · 2024Review
Corrections and comments
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Authors and funding
26 authors at 6 institutions in 2 countries.
Zach H GrayCancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Damayanti ChakrabortyDepartment of Medicine, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
Reuben R DuttweilerCancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Department of Medicine, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
Gulnaz D AlekbaevaCancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Sedona E MurphyDepartment of Medicine, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
Kashish ChetalDepartment of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Fei JiDepartment of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Benjamin I FermanCancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Madison A HonerCancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Zhentian WangDepartment of Biology, Stanford University, Stanford, CA 94305, USA.
Cynthia MyersInstitute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Renhong SunMount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
H Ümit KaniskanMount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Monika Maria TomaNuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Fels Cancer Institute for Personalized Medicine, Temple University School of Medicine, 3420 N. Broad Street, MRB 548, Philadelphia, PA 19140, USA.
Elena A BondarenkoCancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
John N SantoroCancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Christopher MirandaCancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Megan E DillinghamDepartment of Medicine, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
Ran TangDepartment of Medicine, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA; School of Life Science and Technology, Harbin Institute of Technology, 150000 Harbin, China.
Or GozaniDepartment of Biology, Stanford University, Stanford, CA 94305, USA.
Jian JinMount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Tomasz SkorskiNuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Fels Cancer Institute for Personalized Medicine, Temple University School of Medicine, 3420 N. Broad Street, MRB 548, Philadelphia, PA 19140, USA.
Cihangir DuyCancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Hayan LeeCancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Ruslan I SadreyevDepartment of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Johnathan R WhetstineCancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Department of Medicine, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: johnathan.whetstine@fccc.edu.
Fox Chase Cancer Center · USMassachusetts General Hospital · USIcahn School of Medicine at Mount Sinai · USStanford University · USTemple University · USHarvard University · US
Funding
WORD PROCESSING CENTER--COREP30CA006927 · NCI · RESEARCH INST OF FOX CHASE CAN CTR · PI Eric Andrew Ross · 1985 to 2026
$138.8MROLE OF DIETARY CONSTITUENTS ON GENE EXPRESSION IN INTESTINAL EPITHELIUMP30DK040561 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI Elizabeth Austen Lawson, Takara Leah Stanley · 1994 to 2026
$31.6MFunction of Protein Methylation in Chromatin and Signaling RegulationR35GM139569 · NIGMS · STANFORD UNIVERSITY · PI Or P. Gozani · 2021 to 2026
$4.0MUnderstanding the Role of Histone Demethylases and Heterochromatin in Cell CycleR01GM097360 · NIGMS · RESEARCH INST OF FOX CHASE CAN CTR · PI WHETSTINE, JOHNATHAN R. · 2012 to 2020
$3.4MDeciphering Networks Controlling DNA AmplificationR35GM144131 · NIGMS · RESEARCH INST OF FOX CHASE CAN CTR · PI Johnathan R. Whetstine · 2022 to 2026
$2.3MOncogenic tyrosine kinases inhibitors abrogate DNA repair and sensitive leukemias to PARP inhibitorsR01CA244044 · NCI · TEMPLE UNIV OF THE COMMONWEALTH · PI SKORSKI, TOMASZ · 2020 to 2024
$1.9MMolecular Biology and Genetics: Signaling, Epigenetics and Genome MaintenanceT32GM142606 · NIGMS · TEMPLE UNIV OF THE COMMONWEALTH · PI Xavier Grana, Kelly A Whelan · 2021 to 2026
$1.5MNCI NIH HHS P30 CA006927NCI NIH HHS R01 CA244044NIDDK NIH HHS P30 DK040561NIGMS NIH HHS R01 GM097360NIGMS NIH HHS R35 GM139569NIGMS NIH HHS R35 GM144131NIGMS NIH HHS T32 GM142606
Abstract
MLL/KMT2A amplifications and translocations are prevalent in infant, adult, and therapy-induced leukemia. However, the molecular contributor(s) to these alterations are unclear. Here, we demonstrate that histone H3 lysine 9 mono- and di-methylation (H3K9me1/2) balance at the MLL/KMT2A locus regulates these amplifications and rearrangements. This balance is controlled by the crosstalk between lysine demethylase KDM3B and methyltransferase G9a/EHMT2. KDM3B depletion increases H3K9me1/2 levels and reduces CTCF occupancy at the MLL/KMT2A locus, in turn promoting amplification and rearrangements. Depleting CTCF is also sufficient to generate these focal alterations. Furthermore, the chemotherapy doxorubicin (Dox), which associates with therapy-induced leukemia and promotes MLL/KMT2A amplifications and rearrangements, suppresses KDM3B and CTCF protein levels. KDM3B and CTCF overexpression rescues Dox-induced MLL/KMT2A alterations. G9a inhibition in human cells or mice also suppresses MLL/KMT2A events accompanying Dox treatment. Therefore, MLL/KMT2A amplifications and rearrangements are controlled by epigenetic regulators that are tractable drug targets, which has clinical implications.
Indexed as
Epigenesis, GeneticMyeloid-Lymphoid Leukemia ProteinAdultAnimalsDoxorubicinGene RearrangementHistocompatibility AntigensHistone-Lysine N-MethyltransferaseHumansInfantJumonji Domain-Containing Histone DemethylasesLeukemiaLysineMiceTranslocation, GeneticDoxorubicinEHMT2 protein, humanHistocompatibility AntigensHistone-Lysine N-MethyltransferaseJumonji Domain-Containing Histone DemethylasesKDM3B protein, humanKMT2A protein, humanLysineMyeloid-Lymphoid Leukemia ProteinCTCFDNA amplificationdoxorubicinecDNAG9aH3K9meKDM3BKMT2AMLLrearrangements
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