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Blood. 2016 Jan 14;127(2):221-32. doi: 10.1182/blood-2014-12-614503. Epub 2015 Oct 13.

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

Author information

1
Department of Molecular Biotechnology and Health Sciences, Center for Experimental Research and Medical Studies, University of Turin, Turin, Italy;
2
Lymphoma and Genomics Research Program, Institute of Oncology Research, Bellinzona, Switzerland; Dalle Molle Institute for Artificial Intelligence, Bellinzona, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland;
3
Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; Hematology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Cà Granda-Ospedale Maggiore Policlinico, Milan, Italy;
4
Department of Biomedical Informatics, Columbia University College, New York, NY;
5
Città della Salute e della Scienza, Turin, Italy;
6
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY;
7
Lymphoma and Genomics Research Program, Institute of Oncology Research, Bellinzona, Switzerland;
8
Institute of Hematology, University of Perugia, Ospedale S. Maria della Misericordia, S. Andrea delle Fratte, Perugia, Italy;
9
Department of Medical Sciences, University of Turin, Turin, Italy; Human Genetics Foundation, Turin, Italy;
10
Lymphoma and Genomics Research Program, Institute of Oncology Research, Bellinzona, Switzerland; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; and.
11
Department of Molecular Biotechnology and Health Sciences, Center for Experimental Research and Medical Studies, University of Turin, Turin, Italy; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY;
12
Department of Molecular Biotechnology and Health Sciences, Center for Experimental Research and Medical Studies, University of Turin, Turin, Italy; Department of Pathology, New York University Cancer Center, New York University School of Medicine, New York, NY.

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.

PMID:
26463425
DOI:
10.1182/blood-2014-12-614503
[Indexed for MEDLINE]
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