title: MLL-Rearranged Acute Lymphoblastic Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the BCL-2-Specific Antagonist ABT-199.
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.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Juliana M
authors.initials: JM
authors.lastname: Benito
authors.affiliation: Weatherall Institute of Molecular Medicine, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Headington, Oxford OX3 9DS, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Godfrey
authors.affiliation: Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 840-8502, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kojima
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Hogdal
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Wunderlich
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Huimin
authors.initials: H
authors.lastname: Geng
authors.affiliation: Department of Biochemistry, Molecular and Cell Biology, University of Zaragoza, 50018 Zaragoza, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Marzo
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Karine G
authors.initials: KG
authors.lastname: Harutyunyan
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Golfman
authors.affiliation: Weatherall Institute of Molecular Medicine, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Headington, Oxford OX3 9DS, UK.
authors.forename: Phillip
authors.initials: P
authors.lastname: North
authors.affiliation: Weatherall Institute of Molecular Medicine, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Headington, Oxford OX3 9DS, UK.
authors.forename: Jon
authors.initials: J
authors.lastname: Kerry
authors.affiliation: Weatherall Institute of Molecular Medicine, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Headington, Oxford OX3 9DS, UK.
authors.forename: Erica
authors.initials: E
authors.lastname: Ballabio
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York House, Dublin 2, Ireland.
authors.forename: Triona Ní
authors.initials: TN
authors.lastname: Chonghaile
authors.affiliation: Department of Biochemistry, Molecular and Cell Biology, University of Zaragoza, 50018 Zaragoza, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Gonzalo
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
authors.forename: Irmela
authors.initials: I
authors.lastname: Jeremias
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: LaKiesha
authors.initials: L
authors.lastname: Debose
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: O'Brien
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Jacamo
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Park
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Coombes
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Nianxiang
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Thomas
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Department of Oncology Development, AbbVie Inc., North Chicago, IL 60064, USA.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Leverson
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Zweidler-McKay
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Mulloy
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Letai
authors.affiliation: 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.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Milne
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: mkonople@mdanderson.org.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019254:Genes, bcl-2; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D008745:Methylation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C497422:KMT2A protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; C579720:venetoclax
keywords: DOT1L; H3K79 methylation; MLL/AF4; apoptosis pathways; bcl-2 family members; leukemias