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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.

Original publication

DOI

10.1016/j.celrep.2015.12.003

Type

Journal article

Journal

Cell Rep

Publication Date

29/12/2015

Volume

13

Pages

2715 - 2727

Keywords

DOT1L, H3K79 methylation, MLL/AF4, apoptosis pathways, bcl-2 family members, leukemias, Animals, Bridged Bicyclo Compounds, Heterocyclic, Cell Line, Tumor, Genes, bcl-2, Histone-Lysine N-Methyltransferase, Humans, Methylation, Mice, Mice, Inbred NOD, Mice, SCID, Myeloid-Lymphoid Leukemia Protein, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Proto-Oncogene Proteins c-bcl-2, Sulfonamides