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

Journal article

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.

Authors: Benito, J; Godfrey, L; Kojima, K; Hogdal, L; Wunderlich, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Cell reports
• Volume: 13
• Issue: 12
• Pages: 2715-2727
• Publication date: 2015-12-17
• Acceptance date: 2015-11-19
• DOI: 10.1016/j.celrep.2015.12.003
• EISSN: 2211-1247
• Language: English
• Keywords: apoptosis pathways; bcl-2 family members; H3K79 methylation; MLL/AF4; DOT1L; leukemias