TY - JOUR
T1 - Genomic and functional analysis identifies CRKL as an oncogene amplified in lung cancer
AU - Kim, Y. H.
AU - Kwei, K. A.
AU - Girard, L.
AU - Salari, K.
AU - Kao, J.
AU - Pacyna-Gengelbach, M.
AU - Wang, P.
AU - Hernandez-Boussard, T.
AU - Gazdar, A. F.
AU - Petersen, I.
AU - Minna, J. D.
AU - Pollack, J. R.
N1 - Funding Information:
We thank the SFGF for fabrication of microarrays and the SMD for database support. We thank Eon Rios for assistance with flow cytometry analysis. We also thank the members of the Pollack lab for helpful discussion. This work was supported in part by grants from the NIH: R01 CA97139 (JRP), SPORE P50CA70907 (JDM), EDRN U01CA084971 (AFG); DOD VITAL (JDM); Longenbaugh Foundations (JDM); TRDRP (17FT-0062; KAK) and the Deutsche Krebshilfe: 108003 (IP). KS was supported by the Medical Scientist Training Program and is a Paul & Daisy Soros fellow.
PY - 2010/3
Y1 - 2010/3
N2 - DNA amplifications, leading to the overexpression of oncogenes, are a cardinal feature of lung cancer and directly contribute to its pathogenesis. To uncover such novel alterations, we performed an array-based comparative genomic hybridization survey of 128 non-small-cell lung cancer cell lines and tumors. Prominent among our findings, we identified recurrent high-level amplification at cytoband 22q11.21 in 3% of lung cancer specimens, with another 11% of specimens exhibiting low-level gain spanning that locus. The 22q11.21 amplicon core contained eight named genes, only four of which were overexpressed (by transcript profiling) when amplified. Among these, CRKL encodes an adapter protein functioning in signal transduction, best known as a substrate of the BCR-ABL kinase in chronic myelogenous leukemia. RNA-interference-mediated knockdown of CRKL in lung cancer cell lines with (but not without) amplification led to significantly decreased cell proliferation, cell-cycle progression, cell survival, and cell motility and invasion. In addition, overexpression of CRKL in immortalized human bronchial epithelial cells led to enhanced growth factor-independent cell growth. Our findings indicate that amplification and resultant overexpression of CRKL contribute to diverse oncogenic phenotypes in lung cancer, with implications for targeted therapy, and highlight a role of adapter proteins as primary genetic drivers of tumorigenesis.
AB - DNA amplifications, leading to the overexpression of oncogenes, are a cardinal feature of lung cancer and directly contribute to its pathogenesis. To uncover such novel alterations, we performed an array-based comparative genomic hybridization survey of 128 non-small-cell lung cancer cell lines and tumors. Prominent among our findings, we identified recurrent high-level amplification at cytoband 22q11.21 in 3% of lung cancer specimens, with another 11% of specimens exhibiting low-level gain spanning that locus. The 22q11.21 amplicon core contained eight named genes, only four of which were overexpressed (by transcript profiling) when amplified. Among these, CRKL encodes an adapter protein functioning in signal transduction, best known as a substrate of the BCR-ABL kinase in chronic myelogenous leukemia. RNA-interference-mediated knockdown of CRKL in lung cancer cell lines with (but not without) amplification led to significantly decreased cell proliferation, cell-cycle progression, cell survival, and cell motility and invasion. In addition, overexpression of CRKL in immortalized human bronchial epithelial cells led to enhanced growth factor-independent cell growth. Our findings indicate that amplification and resultant overexpression of CRKL contribute to diverse oncogenic phenotypes in lung cancer, with implications for targeted therapy, and highlight a role of adapter proteins as primary genetic drivers of tumorigenesis.
KW - Adapter protein
KW - CRKL
KW - DNA amplification
KW - Genomic profiling
KW - Lung cancer
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U2 - 10.1038/onc.2009.437
DO - 10.1038/onc.2009.437
M3 - Article
C2 - 19966867
AN - SCOPUS:77949424529
SN - 0950-9232
VL - 29
SP - 1421
EP - 1430
JO - Oncogene
JF - Oncogene
IS - 10
ER -