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

Irene Scarfò, Elisa Pellegrino, Elisabetta Mereu, Ivo Kwee, Luca Agnelli, Elisa Bergaggio, Giulia Garaffo, Nicoletta Vitale, Manuel Caputo, Rodolfo Machiorlatti, Paola Circosta, Francesco Abate, Antonella Barreca, Domenico Novero, Susan Mathew, Andrea Rinaldi, Enrico Tiacci, Sara Serra, Silvia Deaglio, Antonino NeriBrunangelo Falini, Raul Rabadan, Francesco Bertoni, Giorgio Inghirami, Roberto Piva, Michela Boi, Ramona Crescenzo, Giuditta Cuccuru, Marcello Gaudiano, Elena Lasorsa, Enzo Medico, Katia Messana, Elisa Spaccarotella, Fabrizio Tabbò, Maria Todaro, Alessandro Fornari, Marco Chilosi, Alberto Zamò, Fabio Facchetti, Silvia Lonardi, Anna De Chiara, Franco Fulciniti, Claudio Doglioni, Maurilio Ponzoni, Katia Todoerti, Claudio Agostinelli, Pier Paolo Piccaluga, Stefano Pileri, Christiane De Wolf-Peeters, Thomas Tousseyn, Peter Van Loo, Eva Geissinger, Hans Konrad Muller-Hermelink, Andreas Rosenwald, Andras Matolcsy, Miguel Angel Piris, Maria E. Rodriguez-Pinilla

Research output: Contribution to journalArticlepeer-review


Anaplastic large-cell lymphoma (ALCL) is a clinical and biological heterogeneous disease that includes systemic anaplastic lymphoma kinase (ALK)-positive and ALKnegative 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 59 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 59 untranslated regions.

Original languageEnglish
Pages (from-to)221-232
Number of pages12
Issue number2
Publication statusPublished - Jan 14 2016

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology


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