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 journalArticle

Abstract

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
JournalBlood
Volume127
Issue number2
DOIs
Publication statusPublished - Jan 14 2016

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Anaplastic Large-Cell Lymphoma
T-cells
Genes
RNA
Untranslated Regions
Terminal Repeat Sequences
Transcription Initiation Site
Cell growth
RNA Sequence Analysis
Biomarkers
Ligases
Luciferases
Gene expression
T-Cell Lymphoma
Amplification
Gene Expression Profiling
Assays
Complementary DNA
Non-Hodgkin's Lymphoma
Disease Progression

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Scarfò, I., Pellegrino, E., Mereu, E., Kwee, I., Agnelli, L., Bergaggio, E., ... Rodriguez-Pinilla, M. E. (2016). Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts. Blood, 127(2), 221-232. https://doi.org/10.1182/blood-2014-12-614503

Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts. / 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, Thomas; Van Loo, Peter; Geissinger, Eva; Muller-Hermelink, Hans Konrad; Rosenwald, Andreas; Matolcsy, Andras; Piris, Miguel Angel; Rodriguez-Pinilla, Maria E.

In: Blood, Vol. 127, No. 2, 14.01.2016, p. 221-232.

Research output: Contribution to journalArticle

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, Boi, M, Crescenzo, R, Cuccuru, G, Gaudiano, M, Lasorsa, E, Medico, E, Messana, K, Spaccarotella, E, Tabbò, F, Todaro, M, Fornari, A, Chilosi, M, Zamò, A, Facchetti, F, Lonardi, S, De Chiara, A, Fulciniti, F, Doglioni, C, Ponzoni, M, Todoerti, K, Agostinelli, C, Piccaluga, PP, Pileri, S, De Wolf-Peeters, C, Tousseyn, T, Van Loo, P, Geissinger, E, Muller-Hermelink, HK, Rosenwald, A, Matolcsy, A, Piris, MA & Rodriguez-Pinilla, ME 2016, 'Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts', Blood, vol. 127, no. 2, pp. 221-232. https://doi.org/10.1182/blood-2014-12-614503
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, Thomas ; Van Loo, Peter ; Geissinger, Eva ; Muller-Hermelink, Hans Konrad ; Rosenwald, Andreas ; Matolcsy, Andras ; Piris, Miguel Angel ; Rodriguez-Pinilla, Maria E. / Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts. In: Blood. 2016 ; Vol. 127, No. 2. pp. 221-232.
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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 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.",
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AU - Pellegrino, Elisa

AU - Mereu, Elisabetta

AU - Kwee, Ivo

AU - Agnelli, Luca

AU - Bergaggio, Elisa

AU - Garaffo, Giulia

AU - Vitale, Nicoletta

AU - Caputo, Manuel

AU - Machiorlatti, Rodolfo

AU - Circosta, Paola

AU - Abate, Francesco

AU - Barreca, Antonella

AU - Novero, Domenico

AU - Mathew, Susan

AU - Rinaldi, Andrea

AU - Tiacci, Enrico

AU - Serra, Sara

AU - Deaglio, Silvia

AU - Neri, Antonino

AU - Falini, Brunangelo

AU - Rabadan, Raul

AU - Bertoni, Francesco

AU - Inghirami, Giorgio

AU - Piva, Roberto

AU - Boi, Michela

AU - Crescenzo, Ramona

AU - Cuccuru, Giuditta

AU - Gaudiano, Marcello

AU - Lasorsa, Elena

AU - Medico, Enzo

AU - Messana, Katia

AU - Spaccarotella, Elisa

AU - Tabbò, Fabrizio

AU - Todaro, Maria

AU - Fornari, Alessandro

AU - Chilosi, Marco

AU - Zamò, Alberto

AU - Facchetti, Fabio

AU - Lonardi, Silvia

AU - De Chiara, Anna

AU - Fulciniti, Franco

AU - Doglioni, Claudio

AU - Ponzoni, Maurilio

AU - Todoerti, Katia

AU - Agostinelli, Claudio

AU - Piccaluga, Pier Paolo

AU - Pileri, Stefano

AU - De Wolf-Peeters, Christiane

AU - Tousseyn, Thomas

AU - Van Loo, Peter

AU - Geissinger, Eva

AU - Muller-Hermelink, Hans Konrad

AU - Rosenwald, Andreas

AU - Matolcsy, Andras

AU - Piris, Miguel Angel

AU - Rodriguez-Pinilla, Maria E.

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N2 - 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.

AB - 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.

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