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Nature. 2015 Oct 15;526(7573):453-7. doi: 10.1038/nature15258. Epub 2015 Oct 7.

Alternative transcription initiation leads to expression of a novel ALK isoform in cancer.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
2
Department of Dermatology, Medical University of Graz, 8010 Graz, Austria.
3
Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
4
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
5
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
6
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
7
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
8
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College/New York Presbyterian Hospital, New York 10065, USA.
9
Institute for Computational Biomedicine, Weill Cornell Medical College/New York Presbyterian Hospital, New York 10065, USA.
10
Institute for Precision Medicine, Weill Cornell Medical College/New York Presbyterian Hospital, New York, USA.
11
Immunology Program, Memorial Sloan Kettering Cancer Center 10065, New York, USA.
12
Herbert Irving Comprehensive Cancer Center, Columbia University Cancer Center, New York 10032, USA.
13
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
14
Department of Medicine, Weill Cornell Medical College, New York 10065, USA.
15
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
16
Department of Neurology, Albert Einstein College of Medicine, New York 10461, USA.
17
Department of Genetics, Albert Einstein College of Medicine, New York 10461, USA.
18
Department of Neuroscience, Albert Einstein College of Medicine, New York 10461, USA.

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.

PMID:
26444240
PMCID:
PMC4807020
DOI:
10.1038/nature15258
[Indexed for MEDLINE]
Free PMC Article

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