title: Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53.
abstract: The transcriptional regulator c-MYC is abnormally overexpressed in many human cancers. Evasion from apoptosis is critical for cancer development, particularly c-MYC-driven cancers. We explored which anti-apoptotic BCL-2 family member (expressed under endogenous regulation) is essential to sustain c-MYC-driven lymphoma growth to reveal which should be targeted for cancer therapy. Remarkably, inducible Cre-mediated deletion of even a single Mcl-1 allele substantially impaired the growth of c-MYC-driven mouse lymphomas. Mutations in p53 could diminish but not obviate the dependency of c-MYC-driven mouse lymphomas on MCL-1. Importantly, targeting of MCL-1 killed c-MYC-driven human Burkitt lymphoma cells, even those bearing mutations in p53. Given that loss of one allele of Mcl-1 is well tolerated in healthy tissues, our results suggest that therapeutic targeting of MCL-1 would be an attractive therapeutic strategy for MYC-driven cancers.
authors.affiliation: The Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia;
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Kelly
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grabow
authors.forename: Stefan P
authors.initials: SP
authors.lastname: Glaser
authors.forename: Leah
authors.initials: L
authors.lastname: Fitzsimmons
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Aubrey
authors.forename: Toru
authors.initials: T
authors.lastname: Okamoto
authors.forename: Liz J
authors.initials: LJ
authors.lastname: Valente
authors.forename: Mikara
authors.initials: M
authors.lastname: Robati
authors.forename: Lin
authors.initials: L
authors.lastname: Tai
authors.forename: W Douglas
authors.initials: WD
authors.lastname: Fairlie
authors.forename: Erinna F
authors.initials: EF
authors.lastname: Lee
authors.forename: Mikael S
authors.initials: MS
authors.lastname: Lindstrom
authors.forename: Klas G
authors.initials: KG
authors.lastname: Wiman
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouillet
authors.forename: Martin
authors.initials: M
authors.lastname: Rowe
authors.forename: Alan B
authors.initials: AB
authors.lastname: Rickinson
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Herold
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics*; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53
keywords: BCL-2; MCL-1; MYC; apoptosis; cancer; p53