1. Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts
- Author
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Scarfò, Irene, Pellegrino, Elisa, Mereu, Elisabetta, Kwee, Ivo, Agnelli, Luca, Bergaggio, Elisa, Garaffo, Giulia, Vitale, Nicoletta, Caputo, Manuel, Machiorlatti, Rodolfo, Circosta, Paola, Abate, Francesco, Barreca, Antonella, Novero, Domenico, Mathew, Susan, Rinaldi, Andrea, Tiacci, Enrico, Serra, Sara, Deaglio, Silvia, Neri, Antonino, Falini, Brunangelo, Rabadan, Raul, Bertoni, Francesco, Inghirami, Giorgio, Piva, Roberto, Boi, Michela, Crescenzo, Ramona, Cuccuru, Giuditta, Gaudiano, Marcello, Lasorsa, Elena, Medico, Enzo, Messana, Katia, Spaccarotella, Elisa, Tabbò, Fabrizio, Todaro, Maria, Fornari, Alessandro, Chilosi, Marco, Zamò, Alberto, Facchetti, Fabio, Lonardi, Silvia, De Chiara, Anna, Fulciniti, Franco, Doglioni, Claudio, Ponzoni, Maurilio, Todoerti, Katia, De Wolf Peeters, Christiane, Tousseyn, Thomas, Van Loo, Peter, Geissinger, Eva, Muller Hermelink, Hans Konrad, Rosenwald, Andreas, Matolcsy, Andras, Piris, Miguel Angel, Rodriguez Pinilla, Maria E., AGOSTINELLI, CLAUDIO, PICCALUGA, PIER PAOLO, PILERI, STEFANO, Scarfò, Irene, Pellegrino, Elisa, Mereu, Elisabetta, Kwee, Ivo, Agnelli, Luca, Bergaggio, Elisa, Garaffo, Giulia, Vitale, Nicoletta, Caputo, Manuel, Machiorlatti, Rodolfo, Circosta, Paola, Abate, Francesco, Barreca, Antonella, Novero, Domenico, Mathew, Susan, Rinaldi, Andrea, Tiacci, Enrico, Serra, Sara, Deaglio, Silvia, Neri, Antonino, Falini, Brunangelo, Rabadan, Raul, Bertoni, Francesco, Inghirami, Giorgio, Piva, Roberto, Boi, Michela, Crescenzo, Ramona, Cuccuru, Giuditta, Gaudiano, Marcello, Lasorsa, Elena, Medico, Enzo, Messana, Katia, Spaccarotella, Elisa, Tabbò, Fabrizio, Todaro, Maria, Fornari, Alessandro, Chilosi, Marco, Zamò, Alberto, Facchetti, Fabio, Lonardi, Silvia, De Chiara, Anna, Fulciniti, Franco, Doglioni, Claudio, Ponzoni, Maurilio, Todoerti, Katia, Agostinelli, Claudio, Piccaluga, Pier Paolo, Pileri, Stefano, De Wolf-Peeters, Christiane, Tousseyn, Thoma, Van Loo, Peter, Geissinger, Eva, Muller-Hermelink, Hans Konrad, Rosenwald, Andrea, Matolcsy, Andra, Piris, Miguel Angel, Rodriguez-Pinilla, Maria E., Scarfò, I, Pellegrino, E, Mereu, E, Kwee, I, Agnelli, L, Bergaggio, E, Garaffo, G, Vitale, N, Caputo, M, Machiorlatti, R, Circosta, P, Abate, F, Barreca, A, Novero, D, Mathew, S, Rinaldi, A, Tiacci, E, Serra, S, Deaglio, S, Neri, A, Falini, B, Rabadan, R, Bertoni, F, Inghirami, G, Piva, R, the European T-Cell Lymphoma Study, Group, Doglioni, C, and Ponzoni, M
- Subjects
0301 basic medicine ,Untranslated region ,Receptor, ErbB-4 ,Messenger ,Mice, SCID ,Biochemistry ,Mice ,0302 clinical medicine ,5' Untranslated Region ,HEK293 Cell ,Mutant Protein ,Mice, Inbred NOD ,hemic and lymphatic diseases ,5' Untranslated RegionsAnimalsCodon ,Anaplastic lymphoma kinase ,Anaplastic Lymphoma Kinase ,NIH 3T3 Cell ,Regulation of gene expression ,TransgenicMolecular Sequence DataMutant ProteinsNIH 3T3 CellsReceptor Protein-Tyrosine KinasesReceptor ,Hematology ,Long terminal repeat ,Large-Cell ,Gene Expression Regulation, Neoplastic ,Receptor Protein-Tyrosine Kinase ,Codon, Nonsense ,030220 oncology & carcinogenesis ,Lymphoma, Large-Cell, Anaplastic ,Human ,Molecular Sequence Data ,Immunology ,ErbB-4RNA ,Mice, Transgenic ,Biology ,03 medical and health sciences ,Complementary DNA ,Animals ,Humans ,RNA, Messenger ,Gene ,NonsenseGene Expression Regulation ,NeoplasticHEK293 CellsHumansLymphoma ,Animal ,Receptor Protein-Tyrosine Kinases ,RNA ,Cell Biology ,Molecular biology ,Gene expression profiling ,HEK293 Cells ,030104 developmental biology ,Inbred NODMice ,NIH 3T3 Cells ,Mutant Proteins ,SCIDMice ,AnaplasticMiceMice ,5' Untranslated Regions ,5' Untranslated RegionsAnimalsCodon, NonsenseGene Expression Regulation, NeoplasticHEK293 CellsHumansLymphoma, Large-Cell, AnaplasticMiceMice, Inbred NODMice, SCIDMice, TransgenicMolecular Sequence DataMutant ProteinsNIH 3T3 CellsReceptor Protein-Tyrosine KinasesReceptor, ErbB-4RNA, Messenger - Abstract
Anaplastic large-cell lymphoma (ALCL) is a clinical and biological heterogeneous disease that includes systemic anaplastic lymphoma kinase (ALK)-positive and ALK-negative entities. To discover biomarkers and/or genes involved in ALK-negative ALCL pathogenesis, we applied the cancer outlier profile analysis algorithm to a gene expression profiling data set including 249 cases of T-cell non-Hodgkin lymphoma and normal T cells. Ectopic coexpression of ERBB4 and COL29A1 genes was detected in 24% of ALK-negative ALCL patients. RNA sequencing and 5' RNA ligase-mediated rapid amplification of complementary DNA ends identified 2 novel ERBB4-truncated transcripts displaying intronic transcription start sites. By luciferase assays, we defined that the expression of ERBB4-aberrant transcripts is promoted by endogenous intronic long terminal repeats. ERBB4 expression was confirmed at the protein level by western blot analysis and immunohistochemistry. Lastly, we demonstrated that ERBB4-truncated forms show oncogenic potentials and that ERBB4 pharmacologic inhibition partially controls ALCL cell growth and disease progression in an ERBB4-positive patient-derived tumorgraft model. In conclusion, we identified a new subclass of ALK-negative ALCL characterized by aberrant expression of ERBB4-truncated transcripts carrying intronic 5' untranslated regions. © 2016 by The American Society of Hematology.
- Published
- 2016