Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement

Cell. 2023 Oct 12;186(21):4528-4545.e18. doi: 10.1016/j.cell.2023.09.009. Epub 2023 Oct 2.

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.

Keywords: CTCF; DNA amplification; G9a; H3K9me; KDM3B; KMT2A; MLL; doxorubicin; ecDNA; rearrangements.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Doxorubicin
  • EHMT2 protein, human
  • Histocompatibility Antigens
  • Histone-Lysine N-Methyltransferase
  • Jumonji Domain-Containing Histone Demethylases
  • KDM3B protein, human
  • Lysine
  • Myeloid-Lymphoid Leukemia Protein
  • KMT2A protein, human