Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer


Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. Here we show that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumours in nude mice. The EML4–ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined; these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. Our data demonstrate that a subset of NSCLC patients may express a transforming fusion kinase that is a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: Gene fusion between EML4 and ALK.
Figure 2: Transforming activity of EML4–ALK variant 1.
Figure 3: Screening of NSCLC specimens for EML4–ALK variant 1 mRNA.
Figure 4: Inhibition of the growth of BA/F3 cells expressing EML4–ALK variant 1 by a chemical inhibitor of ALK.


  1. Jemal, A. et al. Cancer statistics, 2006. CA Cancer J. Clin. 56, 106–130 (2006)

    Article  Google Scholar 

  2. Schiller, J. H. et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N. Engl. J. Med. 346, 92–98 (2002)

    Article  CAS  Google Scholar 

  3. Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004)

    Article  CAS  Google Scholar 

  4. Paez, J. G. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497–1500 (2004)

    Article  ADS  CAS  Google Scholar 

  5. Druker, B. J. et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344, 1031–1037 (2001)

    Article  CAS  Google Scholar 

  6. Pao, W. et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Natl Acad. Sci. USA 101, 13306–13311 (2004)

    Article  ADS  CAS  Google Scholar 

  7. Yoshizuka, N. et al. An alternative transcript derived from the Trio locus encodes a guanosine nucleotide exchange factor with mouse cell-transforming potential. J. Biol. Chem. 279, 43998–44004 (2004)

    Article  CAS  Google Scholar 

  8. Hatanaka, H. et al. Transforming activity of purinergic receptor P2Y, G-protein coupled, 2 revealed by retroviral expression screening. Biochem. Biophys. Res. Commun. 356, 723–726 (2007)

    Article  CAS  Google Scholar 

  9. Choi, Y. L. et al. Identification of a constitutively active mutant of JAK3 by retroviral expression screening. Leuk. Res. 31, 203–209 (2007)

    Article  CAS  Google Scholar 

  10. Fujiwara, S. et al. Transforming activity of the lymphotoxin-β receptor revealed by expression screening. Biochem. Biophys. Res. Commun. 338, 1256–1262 (2005)

    Article  CAS  Google Scholar 

  11. Pollmann, M. et al. Human EML4, a novel member of the EMAP family, is essential for microtubule formation. Exp. Cell Res. 312, 3241–3251 (2006)

    Article  CAS  Google Scholar 

  12. Eichenmuller, B., Everley, P., Palange, J., Lepley, D. & Suprenant, K. A. The human EMAP-like protein-70 (ELP70) is a microtubule destabilizer that localizes to the mitotic apparatus. J. Biol. Chem. 277, 1301–1309 (2002)

    Article  CAS  Google Scholar 

  13. Smith, T. F., Gaitatzes, C., Saxena, K. & Neer, E. J. The WD repeat: a common architecture for diverse functions. Trends Biochem. Sci. 24, 181–185 (1999)

    Article  CAS  Google Scholar 

  14. Morris, S. W. et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 263, 1281–1284 (1994)

    Article  ADS  CAS  Google Scholar 

  15. Shiota, M. et al. Hyperphosphorylation of a novel 80 kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line, AMS3. Oncogene 9, 1567–1574 (1994)

    CAS  PubMed  Google Scholar 

  16. Pulford, K., Morris, S. W. & Turturro, F. Anaplastic lymphoma kinase proteins in growth control and cancer. J. Cell. Physiol. 199, 330–358 (2004)

    Article  CAS  Google Scholar 

  17. Galkin, A. V. et al. Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. Proc. Natl Acad. Sci. USA 104, 270–275 (2007)

    Article  ADS  CAS  Google Scholar 

  18. Donella-Deana, A. et al. Unique substrate specificity of anaplastic lymphoma kinase (ALK): development of phosphoacceptor peptides for the assay of ALK activity. Biochemistry 44, 8533–8542 (2005)

    Article  CAS  Google Scholar 

  19. Hernandez, L. et al. Diversity of genomic breakpoints in TFG-ALK translocations in anaplastic large cell lymphomas: identification of a new TFG-ALKXL chimeric gene with transforming activity. Am. J. Pathol. 160, 1487–1494 (2002)

    Article  CAS  Google Scholar 

  20. Palacious, R. & Steinmetz, M. IL-3 dependent mouse clones that express B-220 surface antigen, contain Ig genes in germ-line configuration, and generate B lymphocytes in vivo.. Cell 41, 727–734 (1985)

    Article  Google Scholar 

  21. Kaul, K. L. Molecular detection of Mycobacterium tuberculosis: impact on patient care. Clin. Chem. 47, 1553–1558 (2001)

    CAS  PubMed  Google Scholar 

  22. Marzec, M. et al. Inhibition of ALK enzymatic activity in T-cell lymphoma cells induces apoptosis and suppresses proliferation and STAT3 phosphorylation independently of Jak3. Lab. Invest. 85, 1544–1554 (2005)

    Article  CAS  Google Scholar 

  23. Li, R. et al. Design and synthesis of 5-aryl-pyridone-carboxamides as inhibitors of anaplastic lymphoma kinase. J. Med. Chem. 49, 1006–1015 (2006)

    Article  CAS  Google Scholar 

  24. Watanabe, S., Itoh, T. & Arai, K. JAK2 is essential for activation of c-fos and c-myc promoters and cell proliferation through the human granulocyte-macrophage colony-stimulating factor receptor in BA/F3 cells. J. Biol. Chem. 271, 12681–12686 (1996)

    Article  CAS  Google Scholar 

  25. Duyster, J., Bai, R. Y. & Morris, S. W. Translocations involving anaplastic lymphoma kinase (ALK). Oncogene 20, 5623–5637 (2001)

    Article  CAS  Google Scholar 

  26. Onishi, M. et al. Applications of retrovirus-mediated expression cloning. Exp. Hematol. 24, 324–329 (1996)

    CAS  PubMed  Google Scholar 

  27. Yamashita, Y. et al. Sak serine/threonine kinase acts as an effector of Tec tyrosine kinase. J. Biol. Chem. 276, 39012–39020 (2001)

    Article  CAS  Google Scholar 

Download references


We thank R. Moriuchi for suggestions.

Author Contributions M.S. and Y.L.C. contributed equally to this work. M.S., S.-i.F., H.W. and H.H. constructed the cDNA library and screened for transforming genes. Y.L.C. sequenced the EML4–ALK cDNA and conducted the experiments with BA/F3 cells. Y.Y. and S.T. searched for EGFR and KRAS mutations. M.E., S.I., K.K., M.B., S.O., S.T., Y.I. and H.A. performed RT–PCR for EML4–ALK transcripts in cancer specimens. T.N., Y. Sohara, Y. Sugiyama and H.M. designed the overall project, and H.M. wrote the manuscript. All authors discussed the results and commented on the manuscript.

The nucleotide sequences of EML4–ALK variant 1 and variant 2 cDNA have been deposited in DDBJ, EMBL and GenBank under the accession numbers AB274722 and AB275889, respectively.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Hiroyuki Mano.

Ethics declarations

Competing interests

Reprints and permissions information is available at The authors declare no competing financial interests.

Supplementary information

Supplementary Informationn

This file contains Supplementary Data, Supplementary Table 1 and Supplementary Figures 1-4 with Legends. (PDF 886 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Soda, M., Choi, Y., Enomoto, M. et al. Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer. Nature 448, 561–566 (2007).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing