title: Alternative transcription initiation leads to expression of a novel ALK isoform in cancer.
abstract: Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in ∼11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novel ALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19, and was termed ALK(ATI). In ALK(ATI)-expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALK(ATI) is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK(ATI) transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALK(ATI) stimulates multiple oncogenic signalling pathways, drives growth-factor-independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK(ATI), suggesting that patients with ALK(ATI)-expressing tumours may benefit from ALK inhibitors. Our findings suggest a novel mechanism of oncogene activation in cancer through de novo alternative transcription initiation.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.|Department of Dermatology, Medical University of Graz, 8010 Graz, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wiesner
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.|Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: William
authors.initials: W
authors.lastname: Lee
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Obenauf
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Leili
authors.initials: L
authors.lastname: Ran
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York 10065, USA.|Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Rajmohan
authors.initials: R
authors.lastname: Murali
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Qi Fan
authors.initials: QF
authors.lastname: Zhang
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Elissa W P
authors.initials: EW
authors.lastname: Wong
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Wenhuo
authors.initials: W
authors.lastname: Hu
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.|Department of Pathology, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Sasinya N
authors.initials: SN
authors.lastname: Scott
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.|Department of Pathology, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Ronak H
authors.initials: RH
authors.lastname: Shah
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Landa
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Button
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lailler
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College/New York Presbyterian Hospital, New York 10065, USA.|Institute for Computational Biomedicine, Weill Cornell Medical College/New York Presbyterian Hospital, New York 10065, USA.|Institute for Precision Medicine, Weill Cornell Medical College/New York Presbyterian Hospital, New York, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sboner
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Gao
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Devan A
authors.initials: DA
authors.lastname: Murphy
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Shipra
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Hollmann
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Borsu
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center 10065, New York, USA.
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University Cancer Center, New York 10032, USA.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York 10065, USA.|Department of Medicine, Weill Cornell Medical College, New York 10065, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Postow
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Ariyan
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York 10065, USA.|Department of Medicine, Weill Cornell Medical College, New York 10065, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Fagin
authors.affiliation: Department of Neurology, Albert Einstein College of Medicine, New York 10461, USA.|Department of Genetics, Albert Einstein College of Medicine, New York 10461, USA.|Department of Neuroscience, Albert Einstein College of Medicine, New York 10461, USA.
authors.forename: Deyou
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.|Department of Pathology, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Klaus J
authors.initials: KJ
authors.lastname: Busam
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.|Department of Pathology, Memorial Sloan Kettering Cancer Center, New York 10065, USA.|Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York 10065, USA.|Department of Medicine, Weill Cornell Medical College, New York 10065, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York 10065, USA.|Department of Medicine, Weill Cornell Medical College, New York 10065, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Chi
mesh_terms: D000483:Alleles; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D057809:HEK293 Cells; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007438:Introns / Q000235:genetics; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008969:Molecular Sequence Data; D008970:Molecular Weight; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D012319:RNA Polymerase II / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D015398:Signal Transduction; D061785:Transcription Initiation, Genetic
chemical_list: D006657:Histones; D007527:Isoenzymes; D012333:RNA, Messenger; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D012319:RNA Polymerase II; D008239:Lysine