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

Authors: Wiesner, T.; Lee, W.; Obenauf, A. C.; Ran, L.; Murali, R.; Zhang, Q.; 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.; Wang, L.; Borsu, L.; Merghoub, T.; Schwartz, G. K.; Postow, M. A.; Ariyan, C. E.; Fagin, J. A.; Zheng, D.; Ladanyi, M.; Busam, K. J.; Berger, M. F.; Chen, Y.; Chi, P.
Article 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 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. © 2015 Macmillan Publishers Limited. All rights reserved.
Journal Title: Nature
Volume: 526
Issue: 7573
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2015-10-15
Start Page: 453
End Page: 457
Language: English
DOI: 10.1038/nature15258
PROVIDER: scopus
PUBMED: 26444240
PMCID: PMC4807020
Notes: Export Date: 2 November 2015 -- Source: Scopus
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MSK Authors
  1. James A Fagin
    107 Fagin
  2. Taha Merghoub
    190 Merghoub
  3. Yu Chen
    67 Chen
  4. Michael Andrew Postow
    182 Postow
  5. Ping Chi
    44 Chi
  6. Marc Ladanyi
    861 Ladanyi
  7. Lu Wang
    139 Wang
  8. Charlotte Eielson Ariyan
    76 Ariyan
  9. Rajmohan Murali
    155 Murali
  10. Wenhuo Hu
    28 Hu
  11. Thomas Wiesner
    38 Wiesner
  12. Michael Forman Berger
    380 Berger
  13. Anna Obenauf
    11 Obenauf
  14. Klaus J Busam
    535 Busam
  15. Leili Ran
    17 Ran
  16. Zhen Cao
    15 Cao
  17. Shipra Shukla
    11 Shukla
  18. William Lee
    38 Lee
  19. Dong Gao
    22 Gao
  20. Wai Pung Elissa Wong
    11 Wong
  21. Ronak Hasmukh Shah
    43 Shah
  22. Sasinya Neka Scott
    66 Scott
  23. Qi Fan Zhang
    2 Zhang
  24. Devan Anne Murphy
    11 Murphy
  25. Julia Leigh Button
    1 Button