MLL-Rearranged Acute Lymphoblastic Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the BCL-2-Specific Antagonist ABT-199

• Published in: Cell reports (Cambridge) Vol. 13; no. 12; pp. 2715 - 2727
• Main Authors: Benito, Juliana M., Godfrey, Laura, Kojima, Kensuke, Hogdal, Leah, Wunderlich, Mark, Geng, Huimin, Marzo, Isabel, Harutyunyan, Karine G., Golfman, Leonard, North, Phillip, Kerry, Jon, Ballabio, Erica, Chonghaile, Triona Ní, Gonzalo, Oscar, Qiu, Yihua, Jeremias, Irmela, Debose, LaKiesha, O’Brien, Eric, Ma, Helen, Zhou, Ping, Jacamo, Rodrigo, Park, Eugene, Coombes, Kevin R., Zhang, Nianxiang, Thomas, Deborah A., O’Brien, Susan, Kantarjian, Hagop M., Leverson, Joel D., Kornblau, Steven M., Andreeff, Michael, Müschen, Markus, Zweidler-McKay, Patrick A., Mulloy, James C., Letai, Anthony, Milne, Thomas A., Konopleva, Marina
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.12.2015; Cell Press; Elsevier
• Subjects: Animals; apoptosis pathways; bcl-2 family members; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cell Line, Tumor; DOT1L; Genes, bcl-2; H3K79 methylation; Histone-Lysine N-Methyltransferase - genetics; Humans; leukemias; Methylation; Mice; Mice, Inbred NOD; Mice, SCID; MLL/AF4; Myeloid-Lymphoid Leukemia Protein - genetics; Myeloid-Lymphoid Leukemia Protein - metabolism; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Sulfonamides - pharmacology; MLL/AF4; apoptosis pathways; bcl-2 family members; leukemias; H3K79 methylation; DOT1L
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.12.003

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. [Display omitted] •MLLr ALL blasts express high levels of BCL-2, BAX, and BIM•MLL/AF4 activates BCL2 through H3K79 methylation•MLLr ALL cells are exquisitely sensitive to BCL-2 antagonist ABT-199•ABT-199 treatment synergizes with H3K79 methylation inhibitors on MLLr samples Therapies designed to exploit specific molecular pathways in aggressive cancers are an exciting area of research. Mutations in the MLL gene cause aggressive incurable leukemias. Benito et al. show that MLL leukemias are highly sensitive to BCL-2 inhibitors, especially when combined with drugs that target mutant MLL complex activity.