title: Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts.
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.
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Center for Experimental Research and Medical Studies, University of Turin, Turin, Italy;
authors.forename: Irene
authors.identifier: http://orcid.org/0000-0002-5545-3248
authors.initials: I
authors.lastname: Scarfò
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Center for Experimental Research and Medical Studies, University of Turin, Turin, Italy;
authors.forename: Elisa
authors.identifier: http://orcid.org/0000-0002-8629-8172
authors.initials: E
authors.lastname: Pellegrino
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Center for Experimental Research and Medical Studies, University of Turin, Turin, Italy;
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mereu
authors.affiliation: Lymphoma and Genomics Research Program, Institute of Oncology Research, Bellinzona, Switzerland; Dalle Molle Institute for Artificial Intelligence, Bellinzona, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland;
authors.forename: Ivo
authors.initials: I
authors.lastname: Kwee
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; Hematology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Cà Granda-Ospedale Maggiore Policlinico, Milan, Italy;
authors.forename: Luca
authors.identifier: http://orcid.org/0000-0003-0582-6170
authors.initials: L
authors.lastname: Agnelli
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Center for Experimental Research and Medical Studies, University of Turin, Turin, Italy;
authors.forename: Elisa
authors.initials: E
authors.lastname: Bergaggio
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Center for Experimental Research and Medical Studies, University of Turin, Turin, Italy;
authors.forename: Giulia
authors.initials: G
authors.lastname: Garaffo
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Center for Experimental Research and Medical Studies, University of Turin, Turin, Italy;
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Vitale
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Center for Experimental Research and Medical Studies, University of Turin, Turin, Italy;
authors.forename: Manuel
authors.initials: M
authors.lastname: Caputo
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Center for Experimental Research and Medical Studies, University of Turin, Turin, Italy;
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Machiorlatti
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Center for Experimental Research and Medical Studies, University of Turin, Turin, Italy;
authors.forename: Paola
authors.initials: P
authors.lastname: Circosta
authors.affiliation: Department of Biomedical Informatics, Columbia University College, New York, NY;
authors.forename: Francesco
authors.initials: F
authors.lastname: Abate
authors.affiliation: Città della Salute e della Scienza, Turin, Italy;
authors.forename: Antonella
authors.initials: A
authors.lastname: Barreca
authors.affiliation: Città della Salute e della Scienza, Turin, Italy;
authors.forename: Domenico
authors.initials: D
authors.lastname: Novero
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY;
authors.forename: Susan
authors.initials: S
authors.lastname: Mathew
authors.affiliation: Lymphoma and Genomics Research Program, Institute of Oncology Research, Bellinzona, Switzerland;
authors.forename: Andrea
authors.initials: A
authors.lastname: Rinaldi
authors.affiliation: Institute of Hematology, University of Perugia, Ospedale S. Maria della Misericordia, S. Andrea delle Fratte, Perugia, Italy;
authors.forename: Enrico
authors.initials: E
authors.lastname: Tiacci
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy; Human Genetics Foundation, Turin, Italy;
authors.forename: Sara
authors.initials: S
authors.lastname: Serra
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy; Human Genetics Foundation, Turin, Italy;
authors.forename: Silvia
authors.initials: S
authors.lastname: Deaglio
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; Hematology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Cà Granda-Ospedale Maggiore Policlinico, Milan, Italy;
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
authors.affiliation: Institute of Hematology, University of Perugia, Ospedale S. Maria della Misericordia, S. Andrea delle Fratte, Perugia, Italy;
authors.forename: Brunangelo
authors.initials: B
authors.lastname: Falini
authors.affiliation: Department of Biomedical Informatics, Columbia University College, New York, NY;
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.affiliation: Lymphoma and Genomics Research Program, Institute of Oncology Research, Bellinzona, Switzerland; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; and.
authors.forename: Francesco
authors.identifier: http://orcid.org/0000-0001-5637-8983
authors.initials: F
authors.lastname: Bertoni
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Center for Experimental Research and Medical Studies, University of Turin, Turin, Italy; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY;
authors.forename: Giorgio
authors.initials: G
authors.lastname: Inghirami
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Center for Experimental Research and Medical Studies, University of Turin, Turin, Italy; Department of Pathology, New York University Cancer Center, New York University School of Medicine, New York, NY.
authors.forename: Roberto
authors.identifier: http://orcid.org/0000-0002-2273-3470
authors.initials: R
authors.lastname: Piva
mesh_terms: D020121:5' Untranslated Regions; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D018389:Codon, Nonsense; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000145:classification / Q000235:genetics* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D066247:Receptor, ErbB-4 / Q000235:genetics* / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D018389:Codon, Nonsense; D050505:Mutant Proteins; D012333:RNA, Messenger; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; C587689:ERBB4 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D066247:Receptor, ErbB-4