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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)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Dot1l ; H3k79 Methylation ; Mll/af4 ; Apoptosis Pathways ; Bcl-2 Family Members ; Leukemias
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Journal Cell Reports
Quellenangaben Volume: 13, Issue: 12, Pages: 2715-2727 Article Number: , Supplement: ,
Publisher Cell Press
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Gene Vector (AGV)