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 language | English |
|---|---|
| Pages (from-to) | 221-232 |
| Number of pages | 12 |
| Journal | Blood |
| Volume | 127 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Jan 14 2016 |
Fingerprint
ASJC Scopus subject areas
- Hematology
- Biochemistry
- Cell Biology
- Immunology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts
AU - Scarfò, Irene
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.
PY - 2016/1/14
Y1 - 2016/1/14
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.
UR - http://www.scopus.com/inward/record.url?scp=84955511756&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84955511756&partnerID=8YFLogxK
U2 - 10.1182/blood-2014-12-614503
DO - 10.1182/blood-2014-12-614503
M3 - Article
C2 - 26463425
AN - SCOPUS:84955511756
VL - 127
SP - 221
EP - 232
JO - Blood
JF - Blood
SN - 0006-4971
IS - 2
ER -