Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer.
The genome of a subset of non-small-cell lung cancers (NSCLC) harbors a small inversion within chromosome 2 that gives rise to a transforming fusion gene, EML4-ALK, which encodes an activated protein tyrosine kinase. Although breakpoints within EML4 have been identified in introns 13 and 20, giving rise to variants 1 and 2, respectively, of EML4-ALK, it has remained unclear whether other isoforms of the fusion gene are present in NSCLC cells. We have now screened NSCLC specimens for other in-frame fusion cDNAs that contain both EML4 and ALK sequences. Two slightly different fusion cDNAs in which exon 6 of EML4 was joined to exon 20 of ALK were each identified in two individuals of the cohort. Whereas one cDNA contained only exons 1 to 6 of EML4 (variant 3a), the other also contained an additional 33-bp sequence derived from intron 6 of EML4 (variant 3b). The protein encoded by the latter cDNA thus contained an insertion of 11 amino acids between the EML4 and ALK sequences of that encoded by the former. Both variants 3a and 3b of EML4-ALK exhibited marked transforming activity in vitro as well as oncogenic activity in vivo. A lung cancer cell line expressing endogenous variant 3 of EML4-ALK underwent cell death on exposure to a specific inhibitor of ALK catalytic activity. These data increase the frequency of EML4-ALK-positive NSCLC tumors and bolster the clinical relevance of this oncogenic kinase.
Choi
Young Lim
YL
Division of Functional Genomics and Pulmonary Medicine, Jichi Medical University, Shimotsukeshi, Tochigi, Japan.
Takeuchi
Kengo
K
Soda
Manabu
M
Inamura
Kentaro
K
Togashi
Yuki
Y
Hatano
Satoko
S
Enomoto
Munehiro
M
Hamada
Toru
T
Haruta
Hidenori
H
Watanabe
Hideki
H
Kurashina
Kentaro
K
Hatanaka
Hisashi
H
Ueno
Toshihide
T
Takada
Shuji
S
Yamashita
Yoshihiro
Y
Sugiyama
Yukihiko
Y
Ishikawa
Yuichi
Y
Mano
Hiroyuki
H
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D016923:Cell Death / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases
C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases