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

Thomas Wiesner, William Lee, Anna C. Obenauf, Leili Ran, Rajmohan Murali, Qi Fan Zhang, Elissa W.P. Wong, Wenhuo Hu, Sasinya N. Scott, Ronak H. Shah, Iñigo Landa, Julia Button, Nathalie Lailler, Andrea Sboner, Dong Gao, Devan A. Murphy, Zhen Cao, Shipra Shukla, Travis J. Hollmann, Lu WangLaetitia Borsu, Taha Merghoub, Gary K. Schwartz, Michael A. Postow, Charlotte E. Ariyan, James A. Fagin, Deyou Zheng, Marc Ladanyi, Klaus J. Busam, Michael F. Berger, Yu Chen, Ping Chi

Research output: Contribution to journalArticle

101 Scopus citations

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 ALKATI. In ALKATI -expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALKATI 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 ALKATI transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALKATI 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 ALKATI, 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.

Original languageEnglish (US)
Pages (from-to)453-457
Number of pages5
JournalNature
Volume526
Issue number7573
DOIs
StatePublished - Oct 15 2015

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    Wiesner, T., Lee, W., Obenauf, A. C., Ran, L., Murali, R., Zhang, Q. F., Wong, E. W. P., Hu, W., Scott, S. N., Shah, R. H., Landa, I., Button, J., Lailler, N., Sboner, A., Gao, D., Murphy, D. A., Cao, Z., Shukla, S., Hollmann, T. J., ... Chi, P. (2015). Alternative transcription initiation leads to expression of a novel ALK isoform in cancer. Nature, 526(7573), 453-457. https://doi.org/10.1038/nature15258