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

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

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) translocat...

Бүрэн тодорхойлолт

Номзүйн дэлгэрэнгүй
Үндсэн зохиолчид: Benito, J, Godfrey, L, Kojima, K, Hogdal, L, Wunderlich, M, Geng, H, Marzo, I, Harutyunyan, K, Golfman, L, North, P, Kerry, J, Ballabio, E, Chonghaile, T, Gonzalo, O, Qiu, Y, Jeremias, I, Debose, L, O'Brien, E, Ma, H, Zhou, P, Jacamo, R, Park, E, Coombes, K, Zhang, N, Thomas, D, O'Brien, S, Kantarjian, H, Leverson, J, Kornblau, S, Andreeff, M, Müschen, M, Zweidler-McKay, P, Mulloy, J, Letai, A, Milne, T, Konopleva, M
Формат: Journal article
Хэл сонгох:English
Хэвлэсэн: Cell Press 2015
Тодорхойлолт
Тойм: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.

Ижил төстэй зүйлс