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(American Journal of Pathology. 2002;160:1487-1494.)
© 2002 American Society for Investigative Pathology

Regular Articles

Diversity of Genomic Breakpoints in TFG-ALK Translocations in Anaplastic Large Cell Lymphomas

Identification of a New TFG-ALKXL Chimeric Gene with Transforming Activity

Luis Hernández*, Sílvia Beà{dagger}, Beatriz Bellosillo{dagger}, Magda Pinyol{dagger}, Brunangelo Falini{ddagger}, Antonino Carbone§, German Ott, Andreas Rosenwald, Alberto Fernández*, Karen Pulford||, David Mason||, Stephan W. Morris**, Eugenio Santos* and Elias Campo{dagger}

From the Centro de Investigación delCáncer,* Centro Superior de InvestigacionesCientíficas-University of Salamanca, Salamanca, Spain; theLaboratory of Pathology,{dagger} Hospital Clinic,Institut d’Investigacions Biomediques August Pi i Sunyer, Universityof Barcelona, Barcelona, Spain; Institute ofHematology,{ddagger} Perugia University, Perugia,Italy; the Centro di Riferimento Oncologico, National Cancer Institute,Aviano,§ Aviano, Italy; the Institute ofPathology, University of Würzburg,Würzburg, Germany; the Leukemia Research FundImmunodiagnostics Unit,|| Nuffield Department of ClinicalBiochemistry and Cellular Science, John Radcliffe Hospital, Oxford,United Kingdom; and the Departments of Pathology andHematology-Oncology,** St. Jude Children’sResearch Hospital, Memphis, Tennessee

Anaplastic large cell lymphomas are associated with chromosomal aberrations involving the anaplastic lymphoma kinase (ALK) gene at 2p23 that result in the expression of novel chimeric ALK proteins with transforming properties. In most of these tumors, the t(2;5)(p23;q35) generates the NPM-ALK fusion gene. However, several studies have now demonstrated that genes other than NPM may be fused to the ALK gene. We have recently described two different ALK rearrangements involving the TRK-fused gene (TFG) in which the same portion of ALK was fused to different length fragments of the 5' TFG region. These two rearrangements encoded chimeric proteins of 85 kd (TFG-ALKS) and 97 kd (TFG-ALKL), respectively. In this study, we have identified a new ALK rearrangement in which the catalytic domain of ALK was fused to a larger fragment of the TFG gene (TFG-ALKXL), encoding for a fusion protein of 113 kd. Genomic analysis of these three TFG-ALK rearrangements revealed that the TFG breakpoints occur at introns 3, 4, and 5, respectively, whereas the ALK breakpoints always occur in the same intron. No homologous regions or known recombination sequences were found in these regions. Transfection experiments using NIH-3T3 fibroblasts showed a similar transforming efficiency of TFG-ALK variants compared with NPM-ALK. In addition, in common with NPM-ALK, the TFG-ALK proteins formed stable complexes with the signaling proteins Grb2, Shc, and PLC-{gamma}. In conclusion, these findings indicate that the TFG may use a variety of intronic breakpoints in ALK rearrangements generating fusion proteins of different molecular weights, but with similar transforming potential than NPM-ALK.




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