title: The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia.
abstract: Translocations of the mixed lineage leukemia (MLL) gene occur in 60% to 80% of all infant acute leukemias and are markers of poor prognosis. MLL-AF9 and other MLL fusion proteins aberrantly recruit epigenetic regulatory proteins, including histone deacetylases (HDAC), histone methyltransferases, bromodomain-containing proteins, and transcription elongation factors to mediate chromatin remodeling and regulate tumorigenic gene expression programs. We conducted a small-molecule inhibitor screen to test the ability of candidate pharmacologic agents targeting epigenetic and transcriptional regulatory proteins to induce apoptosis in leukemic cells derived from genetically engineered mouse models of MLL-AF9-driven acute myeloid leukemia (AML). We found that the CDK inhibitor dinaciclib and HDAC inhibitor panobinostat were the most potent inducers of apoptosis in short-term in vitro assays. Treatment of MLL-rearranged leukemic cells with dinaciclib resulted in rapidly decreased expression of the prosurvival protein Mcl-1, and accordingly, overexpression of Mcl-1 protected AML cells from dinaciclib-induced apoptosis. Administration of dinaciclib to mice bearing MLL-AF9-driven human and mouse leukemias elicited potent antitumor responses and significantly prolonged survival. Collectively, these studies highlight a new therapeutic approach to potentially overcome the resistance of MLL-rearranged AML to conventional chemotherapies and prompt further clinical evaluation of CDK inhibitors in AML patients harboring MLL fusion proteins.
authors.affiliation: Gene Regulation Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia.
authors.forename: Adele
authors.initials: A
authors.lastname: Baker
authors.affiliation: Gene Regulation Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia. Monash Haematology, Monash Health, Clayton, Australia.
authors.forename: Gareth P
authors.initials: GP
authors.lastname: Gregory
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Inge
authors.initials: I
authors.lastname: Verbrugge
authors.affiliation: Gene Regulation Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia.
authors.forename: Lev
authors.initials: L
authors.lastname: Kats
authors.affiliation: Gene Regulation Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, Australia.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Hilton
authors.affiliation: Gene Regulation Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, Australia.
authors.forename: Eva
authors.initials: E
authors.lastname: Vidacs
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Erwin M
authors.initials: EM
authors.lastname: Lee
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.affiliation: Gene Regulation Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia. Monash Haematology, Monash Health, Clayton, Australia. School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing, & Health Sciences, Monash University, Clayton, Australia. ricky.johnstone@petermac.org Jake.Shortt@monashhealth.org.
authors.forename: Jake
authors.initials: J
authors.lastname: Shortt
authors.affiliation: Gene Regulation Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia. ricky.johnstone@petermac.org Jake.Shortt@monashhealth.org.
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D003497:Cyclic N-Oxides; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors*; D019008:Drug Resistance, Neoplasm; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007212:Indolizines; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D000077767:Panobinostat; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D006877:Hydroxamic Acids; D007211:Indoles; D007212:Indolizines; C497422:KMT2A protein, human; C474558:MLL-AF9 fusion protein, human; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011726:Pyridinium Compounds; D051788:Myeloid-Lymphoid Leukemia Protein; C553669:dinaciclib; D000077767:Panobinostat; D011495:Histone-Lysine N-Methyltransferase; D042863:Cyclin-Dependent Kinase 9