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 Wang & 12 others Laetitia 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

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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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Protein Isoforms
Neoplasms
Transcription Initiation Site
Oncogenes
anaplastic lymphoma kinase
RNA Polymerase II
Protein-Tyrosine Kinases
Introns
Transcriptional Activation
Chromatin
Melanoma
Intercellular Signaling Peptides and Proteins
Carcinogenesis
Phosphotransferases
Molecular Weight
Alleles
Cell Proliferation
Mutation
Proteins

ASJC Scopus subject areas

  • General

Cite this

Wiesner, T., Lee, W., Obenauf, A. C., Ran, L., Murali, R., Zhang, Q. F., ... 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

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

In: Nature, Vol. 526, No. 7573, 15.10.2015, p. 453-457.

Research output: Contribution to journalArticle

Wiesner, T, Lee, W, Obenauf, AC, Ran, L, Murali, R, Zhang, QF, Wong, EWP, Hu, W, Scott, SN, Shah, RH, Landa, I, Button, J, Lailler, N, Sboner, A, Gao, D, Murphy, DA, Cao, Z, Shukla, S, Hollmann, TJ, Wang, L, Borsu, L, Merghoub, T, Schwartz, GK, Postow, MA, Ariyan, CE, Fagin, JA, Zheng, D, Ladanyi, M, Busam, KJ, Berger, MF, Chen, Y & Chi, P 2015, 'Alternative transcription initiation leads to expression of a novel ALK isoform in cancer', Nature, vol. 526, no. 7573, pp. 453-457. https://doi.org/10.1038/nature15258
Wiesner T, Lee W, Obenauf AC, Ran L, Murali R, Zhang QF et al. Alternative transcription initiation leads to expression of a novel ALK isoform in cancer. Nature. 2015 Oct 15;526(7573):453-457. https://doi.org/10.1038/nature15258
Wiesner, Thomas ; Lee, William ; Obenauf, Anna C. ; Ran, Leili ; Murali, Rajmohan ; Zhang, Qi Fan ; Wong, Elissa W P ; Hu, Wenhuo ; Scott, Sasinya N. ; Shah, Ronak H. ; Landa, Iñigo ; Button, Julia ; Lailler, Nathalie ; Sboner, Andrea ; Gao, Dong ; Murphy, Devan A. ; Cao, Zhen ; Shukla, Shipra ; Hollmann, Travis J. ; Wang, Lu ; Borsu, Laetitia ; Merghoub, Taha ; Schwartz, Gary K. ; Postow, Michael A. ; Ariyan, Charlotte E. ; Fagin, James A. ; Zheng, Deyou ; Ladanyi, Marc ; Busam, Klaus J. ; Berger, Michael F. ; Chen, Yu ; Chi, Ping. / Alternative transcription initiation leads to expression of a novel ALK isoform in cancer. In: Nature. 2015 ; Vol. 526, No. 7573. pp. 453-457.
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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.",
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AU - Wiesner, Thomas

AU - Lee, William

AU - Obenauf, Anna C.

AU - Ran, Leili

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AU - Zhang, Qi Fan

AU - Wong, Elissa W P

AU - Hu, Wenhuo

AU - Scott, Sasinya N.

AU - Shah, Ronak H.

AU - Landa, Iñigo

AU - Button, Julia

AU - Lailler, Nathalie

AU - Sboner, Andrea

AU - Gao, Dong

AU - Murphy, Devan A.

AU - Cao, Zhen

AU - Shukla, Shipra

AU - Hollmann, Travis J.

AU - Wang, Lu

AU - Borsu, Laetitia

AU - Merghoub, Taha

AU - Schwartz, Gary K.

AU - Postow, Michael A.

AU - Ariyan, Charlotte E.

AU - Fagin, James A.

AU - Zheng, Deyou

AU - Ladanyi, Marc

AU - Busam, Klaus J.

AU - Berger, Michael F.

AU - Chen, Yu

AU - Chi, Ping

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N2 - 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.

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