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Benito, J.M.* ; Godfrey, L.* ; Kojima, K.* ; Hogdal, L.* ; Wunderlich, M.* ; Geng, H.* ; Marzo, I.* ; Harutyunyan, K.G.* ; Golfman, L.* ; North, P.* ; Kerry, J.* ; Ballabio, E.* ; Ni Chonghaile, T.* ; Gonzalo, O.* ; Qiu, Y.* ; Jeremias, I. ; Debose, L.* ; O'Brien, E.T.* ; Ma, H.C.* ; Zhou, P.* ; Jacamo, R.* ; Park, E.* ; Coombes, K.R.* ; Zhang, N.* ; Thomas, D.A.* ; O'Brien, S.J.* ; Kantarjian, H.M.* ; Leverson, J.D.* ; Kornblau, S.M.* ; Andreeff, M.* ; Mueschen, M.* ; Zweidler-McKay, P.A.* ; Mulloy, J.C.* ; Letai, A.G.* ; Milne, T.A.* ; Konopleva, M.*

MLL-rearranged acute lymphoblastic leukemias activate BCL-2 through H3K79 methylation and are sensitive to the BCL-2-specific antagonist ABT-199.

Cell Rep. 13, 2715-2727 (2015)

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Targeted therapies designed to exploit specific molecular pathways in aggressive cancers are an exciting area of current research. Mixed Lineage Leukemia (MLL) mutations such as the t(4;11) translocation cause aggressive leukemias that are refractory to conventional treatment. The t(4;11) translocation produces an MLL/AF4 fusion protein that activates key target genes through both epigenetic and transcriptional elongation mechanisms. In this study, we show that t(4;11) patient cells express high levels of BCL-2 and are highly sensitive to treatment with the BCL-2-specific BH3 mimetic ABT-199. We demonstrate that MLL/AF4 specifically upregulates the BCL-2 gene but not other BCL-2 family members via DOT1L-mediated H3K79me2/3. We use this information to show that a t(4;11) cell line is sensitive to a combination of ABT-199 and DOT1L inhibitors. In addition, ABT-199 synergizes with standard induction-type therapy in a xenotransplant model, advocating for the introduction of ABT-199 into therapeutic regimens for MLL-rearranged leukemias.

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