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Cell Rep. 2015 Dec 29;13(12):2715-27. doi: 10.1016/j.celrep.2015.12.003. Epub 2015 Dec 17.

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

Author information

1
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2
Weatherall Institute of Molecular Medicine, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Headington, Oxford OX3 9DS, UK.
3
Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 840-8502, Japan.
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
5
Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
6
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
7
Department of Biochemistry, Molecular and Cell Biology, University of Zaragoza, 50018 Zaragoza, Spain.
8
Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
9
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York House, Dublin 2, Ireland.
10
German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
11
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
12
Department of Oncology Development, AbbVie Inc., North Chicago, IL 60064, USA.
13
Weatherall Institute of Molecular Medicine, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Headington, Oxford OX3 9DS, UK. Electronic address: thomas.milne@imm.ox.ac.uk.
14
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: mkonople@mdanderson.org.

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:

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

PMID:
26711339
PMCID:
PMC4700051
DOI:
10.1016/j.celrep.2015.12.003
[Indexed for MEDLINE]
Free PMC Article

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