Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement.

Gray ZH., Chakraborty D., Duttweiler RR., Alekbaeva GD., Murphy SE., Chetal K., Ji F., Ferman BI., Honer MA., Wang Z., Myers C., Sun R., Kaniskan HÜ., Toma MM., Bondarenko EA., Santoro JN., Miranda C., Dillingham ME., Tang R., Gozani O., Jin J., Skorski T., Duy C., Lee H., Sadreyev RI., Whetstine JR.

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.

DOI

10.1016/j.cell.2023.09.009

Type

Journal article

Journal

Cell

Publication Date

10/2023

Volume

186

Pages

4528 - 4545.e18

Addresses

Cancer 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.

Keywords

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

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