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

Juliana M. Benito, Laura Godfrey, Kensuke Kojima, Leah Hogdal, Mark Wunderlich, Huimin Geng, Isabel Marzo, Karine G. Harutyunyan, Leonard Golfman, Phillip North, Jon Kerry, Erica Ballabio, Triona Ní Chonghaile, Oscar Gonzalo, Yihua Qiu, Irmela Jeremias, La Kiesha Debose, Eric O'Brien, Helen Ma, Ping ZhouRodrigo Jacamo, Eugene Park, Kevin R. Coombes, Nianxiang Zhang, Deborah A. Thomas, Susan O'Brien, Hagop M. Kantarjian, Joel D. Leverson, Steven M. Kornblau, Michael Andreeff, Markus Müschen, Patrick A. Zweidler-McKay, James C. Mulloy, Anthony Letai, Thomas A. Milne, Marina Konopleva

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

Abstract

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. 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.

Original languageEnglish
Pages (from-to)2715-2727
Number of pages13
JournalCell Reports
Volume13
Issue number12
DOIs
StatePublished - 29 Dec 2015
Externally publishedYes

Keywords

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

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