title: Systematic chemical and molecular profiling of MLL-rearranged infant acute lymphoblastic leukemia reveals efficacy of romidepsin.
abstract: To address the poor prognosis of mixed lineage leukemia (MLL)-rearranged infant acute lymphoblastic leukemia (iALL), we generated a panel of cell lines from primary patient samples and investigated cytotoxic responses to contemporary and novel Food and Drug Administration-approved chemotherapeutics. To characterize representation of primary disease within cell lines, molecular features were compared using RNA-sequencing and cytogenetics. High-throughput screening revealed variable efficacy of currently used drugs, however identified consistent efficacy of three novel drug classes: proteasome inhibitors, histone deacetylase inhibitors and cyclin-dependent kinase inhibitors. Gene expression of drug targets was highly reproducible comparing iALL cell lines to matched primary specimens. Histone deacetylase inhibitors, including romidepsin (ROM), enhanced the activity of a key component of iALL therapy, cytarabine (ARAC) in vitro and combined administration of ROM and ARAC to xenografted mice further reduced leukemia burden. Molecular studies showed that ROM reduces expression of cytidine deaminase, an enzyme involved in ARAC deactivation, and enhances the DNA damage-response to ARAC. In conclusion, we present a valuable resource for drug discovery, including the first systematic analysis of transcriptome reproducibility in vitro, and have identified ROM as a promising therapeutic for MLL-rearranged iALL.
authors.affiliation: Division of Children's Leukaemia and Cancer Research, Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: M N
authors.initials: MN
authors.lastname: Cruickshank
authors.affiliation: Division of Children's Leukaemia and Cancer Research, Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Ford
authors.affiliation: Division of Children's Leukaemia and Cancer Research, Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: L C
authors.initials: LC
authors.lastname: Cheung
authors.affiliation: Division of Children's Leukaemia and Cancer Research, Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Heng
authors.affiliation: Division of Children's Leukaemia and Cancer Research, Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Singh
authors.affiliation: Division of Children's Leukaemia and Cancer Research, Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Wells
authors.affiliation: ACRF Drug Discovery Centre for Childhood Cancer, Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: T W
authors.initials: TW
authors.lastname: Failes
authors.affiliation: ACRF Drug Discovery Centre for Childhood Cancer, Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: G M
authors.initials: GM
authors.lastname: Arndt
authors.affiliation: GlaxoSmithKline, Medicines Research Centre, Stevenage, UK.
authors.forename: N
authors.initials: N
authors.lastname: Smithers
authors.affiliation: GlaxoSmithKline, Medicines Research Centre, Stevenage, UK.
authors.forename: R K
authors.initials: RK
authors.lastname: Prinjha
authors.affiliation: Centre for Biostatistics, Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Anderson
authors.affiliation: McCusker Charitable Foundation Bioinformatics Centre, Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: K W
authors.initials: KW
authors.lastname: Carter
authors.affiliation: McCusker Charitable Foundation Bioinformatics Centre, Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: A M
authors.initials: AM
authors.lastname: Gout
authors.affiliation: McCusker Charitable Foundation Bioinformatics Centre, Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Lassmann
authors.affiliation: Department of Haematology, PathWest Laboratory Medicine WA, Fiona Stanley Hospital, Perth, Australia.|School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia.
authors.forename: J
authors.initials: J
authors.lastname: O'Reilly
authors.affiliation: Division of Children's Leukaemia and Cancer Research, Telethon Kids Institute, University of Western Australia, Perth, Australia.|Department of Haematology and Oncology, Princess Margaret Hospital for Children, Perth, Australia.|School of Paediatrics and Child Health, University of Western Australia, Perth, Australia.
authors.forename: C H
authors.initials: CH
authors.lastname: Cole
authors.affiliation: Division of Children's Leukaemia and Cancer Research, Telethon Kids Institute, University of Western Australia, Perth, Australia.|Department of Haematology and Oncology, Princess Margaret Hospital for Children, Perth, Australia.|School of Paediatrics and Child Health, University of Western Australia, Perth, Australia.
authors.forename: R S
authors.initials: RS
authors.lastname: Kotecha
authors.affiliation: Division of Children's Leukaemia and Cancer Research, Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: U R
authors.initials: UR
authors.lastname: Kees
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D047630:Depsipeptides / Q000494:pharmacology*; D015321:Gene Rearrangement; D064593:Heterografts; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology*; D061988:Proteasome Inhibitors / Q000494:pharmacology
chemical_list: D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D061988:Proteasome Inhibitors; D051788:Myeloid-Lymphoid Leukemia Protein; C087123:romidepsin; D018844:Cyclin-Dependent Kinases