Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement

Zach H. Gray, Damayanti Chakraborty, Reuben R. Duttweiler, Gulnaz D. Alekbaeva, Sedona E. Murphy, Kashish Chetal, Fei Ji, Benjamin I. Ferman, Madison A. Honer, Zhentian Wang, Cynthia Myers, Renhong Sun, H. Ümit Kaniskan, Monika Maria Toma, Elena A. Bondarenko, John N. Santoro, Christopher Miranda, Megan E. Dillingham, Ran Tang, Or GozaniJian Jin, Tomasz Skorski, Cihangir Duy, Hayan Lee, Ruslan I. Sadreyev, Johnathan R. Whetstine

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish
Pages (from-to)4528-4545.e18
JournalCell
Volume186
Issue number21
DOIs
StatePublished - Oct 12 2023

Keywords

  • Adult
  • Animals
  • Doxorubicin/pharmacology
  • Epigenesis, Genetic
  • Gene Rearrangement
  • Histocompatibility Antigens
  • Histone-Lysine N-Methyltransferase/genetics
  • Humans
  • Infant
  • Jumonji Domain-Containing Histone Demethylases/genetics
  • Leukemia/metabolism
  • Lysine/metabolism
  • Mice
  • Myeloid-Lymphoid Leukemia Protein/genetics
  • Translocation, Genetic

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