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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 publication




Journal article



Publication Date





4528 - 4545.e18


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.


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