Cell Reports
Volume 13, Issue 12, 29 December 2015, Pages 2715-2727
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Article
MLL-Rearranged Acute Lymphoblastic Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the BCL-2-Specific Antagonist ABT-199

https://doi.org/10.1016/j.celrep.2015.12.003Get rights and content
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Highlights

  • 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

Summary

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.

Keywords

apoptosis pathways
leukemias
bcl-2 family members
MLL/AF4
DOT1L
H3K79 methylation

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This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).