Cell Reports (Dec 2015)
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,
- LaKiesha Debose,
- Eric O’Brien,
- Helen Ma,
- Ping Zhou,
- Rodrigo 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
Affiliations
- Juliana M. Benito
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Laura Godfrey
- Weatherall Institute of Molecular Medicine, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Headington, Oxford OX3 9DS, UK
- Kensuke Kojima
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 840-8502, Japan
- Leah Hogdal
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Mark Wunderlich
- Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
- Huimin Geng
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
- Isabel Marzo
- Department of Biochemistry, Molecular and Cell Biology, University of Zaragoza, 50018 Zaragoza, Spain
- Karine G. Harutyunyan
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Leonard Golfman
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Phillip North
- Weatherall Institute of Molecular Medicine, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Headington, Oxford OX3 9DS, UK
- Jon Kerry
- Weatherall Institute of Molecular Medicine, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Headington, Oxford OX3 9DS, UK
- Erica Ballabio
- Weatherall Institute of Molecular Medicine, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Headington, Oxford OX3 9DS, UK
- Triona Ní Chonghaile
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York House, Dublin 2, Ireland
- Oscar Gonzalo
- Department of Biochemistry, Molecular and Cell Biology, University of Zaragoza, 50018 Zaragoza, Spain
- Yihua Qiu
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Irmela Jeremias
- German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany
- LaKiesha Debose
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Eric O’Brien
- Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
- Helen Ma
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Ping Zhou
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Rodrigo Jacamo
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Eugene Park
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
- Kevin R. Coombes
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Nianxiang Zhang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Deborah A. Thomas
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Susan O’Brien
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Hagop M. Kantarjian
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Joel D. Leverson
- Department of Oncology Development, AbbVie Inc., North Chicago, IL 60064, USA
- Steven M. Kornblau
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Michael Andreeff
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Markus Müschen
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
- Patrick A. Zweidler-McKay
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- James C. Mulloy
- Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
- Anthony Letai
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Thomas A. Milne
- Weatherall Institute of Molecular Medicine, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Headington, Oxford OX3 9DS, UK
- Marina Konopleva
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- DOI
- https://doi.org/10.1016/j.celrep.2015.12.003
- Journal volume & issue
-
Vol. 13,
no. 12
pp. 2715 – 2727
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.
Keywords
