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 Gozani, Jian Jin, Tomasz Skorski, Cihangir Duy, Hayan Lee, Ruslan I Sadreyev, Johnathan R Whetstine
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...
October 12, 2023: Cell