Anaplastic Large Cell Lymphoma (ALCL) is a clinical and biological heterogeneous disease including systemic 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 (COPA) algorithm to a gene expression profiling data set including 249 cases of T-cell non-Hodgkin lymphoma and normal T-cells. Ectopic co-expression of ERBB4 and COL29A1 genes was detected in 24% of ALK negative ALCL patients. RNA sequencing and 5'RNA Ligase-Mediated Rapid Amplification of cDNA Ends (RLM-RACE) identified two 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 (LTRs). ERBB4 expression was confirmed at protein level by western blotting and immunohistochemistry. Finally, we demonstrated that the expression of ERBB4 truncated forms show oncogenic potentials and that ERBB4 pharmacological 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'UTRs.

Identification of a new subclass of ALK negative ALCL expressing aberrant levels of ERBB4 transcripts / I. Scarfò, E. Pellegrino, E. Mereu, I. Kwee, L. Agnelli, E. Bergaggio, G. Garaffo, N. Vitale, M. Caputo, R. Machiorlatti, P. Circosta, F. Abate, A. Barreca, D. Novero, S. Mathew, A. Rinaldi, E. Tiacci, S. Serra, S. Deaglio, A. Neri, B. Falini, R. Rabadan, F. Bertoni, G. Inghirami, R. Piva. - In: BLOOD. - ISSN 0006-4971. - (2015 Oct 13). [Epub ahead of print] [10.1182/blood-2014-12-614503]

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

L. Agnelli;F. Abate;A. Neri;
2015-10-13

Abstract

Anaplastic Large Cell Lymphoma (ALCL) is a clinical and biological heterogeneous disease including systemic 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 (COPA) algorithm to a gene expression profiling data set including 249 cases of T-cell non-Hodgkin lymphoma and normal T-cells. Ectopic co-expression of ERBB4 and COL29A1 genes was detected in 24% of ALK negative ALCL patients. RNA sequencing and 5'RNA Ligase-Mediated Rapid Amplification of cDNA Ends (RLM-RACE) identified two 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 (LTRs). ERBB4 expression was confirmed at protein level by western blotting and immunohistochemistry. Finally, we demonstrated that the expression of ERBB4 truncated forms show oncogenic potentials and that ERBB4 pharmacological 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'UTRs.
Settore MED/15 - Malattie del Sangue
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/327047
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