Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts.

TitleIdentification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts.
Publication TypeJournal Article
Year of Publication2016
AuthorsScarfò 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
Corporate AuthorsEuropean T-Cell Lymphoma Study Group
JournalBlood
Volume127
Issue2
Pagination221-32
Date Published2016 Jan 14
ISSN1528-0020
Keywords5' Untranslated Regions, Anaplastic Lymphoma Kinase, Animals, Codon, Nonsense, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Lymphoma, Large-Cell, Anaplastic, Mice, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, Molecular Sequence Data, Mutant Proteins, NIH 3T3 Cells, Receptor Protein-Tyrosine Kinases, Receptor, ErbB-4, RNA, 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.

DOI10.1182/blood-2014-12-614503
Alternate JournalBlood
PubMed ID26463425
Related Faculty: 
Giorgio Inghirami, M.D.

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