Gene expression profiling uncovers molecular classifiers for the recognition of anaplastic large-cell lymphoma within peripheral T-cell neoplasms

Roberto Piva, Luca Agnelli, Elisa Pellegrino, Katia Todoerti, Valentina Grosso, Ilaria Tamagno, Alessandro Fornari, Barbara Martinoglio, Enzo Medico, Alberto Zamò, Fabio Facchetti, Maurilio Ponzoni, Eva Geissinger, Andreas Rosenwald, Hans Konrad Müller-Hermelink, Christiane De Wolf-Peeters, Pier Paolo Piccaluga, Stefano Pileri, Antonino Neri, Giorgio Inghirami

Research output: Contribution to journalArticle

Abstract

Purpose: To unravel the regulatory network underlying nucleophosmin- anaplastic lymphoma kinase (NPM-ALK) -mediated lymphomagenesis of anaplastic large-cell lymphoma (ALCL) and to discover diagnostic genomic classifiers for the recognition of patients with ALK-positive and ALK-negative ALCL among T-cell non-Hodgkin's lymphoma (T-NHL). Patients and Methods: The transcriptome of NPM-ALK-positive ALCL cell lines was characterized by silencing the expression of ALK or STAT3, a major effector of ALK oncogenic activity. Gene expression profiling (GEP) was performed in a series of systemic primary T-NHL (n = 70), including a set of ALK-positive and ALK-negative ALCL (n = 36). Genomic classifiers for ALK-positive and ALK-negative ALCL were generated by prediction analyses and validated by quantitative reverse-transcriptase polymerase chain reaction and/or immunohistochemistry. Results: In ALCL cell lines, two thirds of ALK-regulated genes were concordantly dependent on STAT3 expression. GEP of systemic primary T-NHL significantly clustered ALK-positive ALCL samples in a separate subgroup, underscoring the relevance of in vitro ALK/STAT3 signatures. A set of genomic classifiers for ALK-positive ALCL and for ALCL were identified by prediction analyses. These gene clusters were instrumental for the distinction of ALK-negative ALCL from peripheral T-cell lymphomas not otherwise specified (PTCLs-NOS) and angioimmunoblastic lymphomas. Conclusion: We proved that experimentally controlled GEP in ALCL cell lines represents a powerful tool to identify meaningful signaling networks for the recognition of systemic primary T-NHL. The identification of a molecular signature specific for ALCL suggests that these T-NHLs may represent a unique entity discernible from other PTCLs, and that a restricted number of genes can be instrumental for clinical stratification and, possibly, therapy of T-NHL.

Original languageEnglish
Pages (from-to)1583-1590
Number of pages8
JournalJournal of Clinical Oncology
Volume28
Issue number9
DOIs
Publication statusPublished - Mar 20 2010

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Piva, R., Agnelli, L., Pellegrino, E., Todoerti, K., Grosso, V., Tamagno, I., Fornari, A., Martinoglio, B., Medico, E., Zamò, A., Facchetti, F., Ponzoni, M., Geissinger, E., Rosenwald, A., Müller-Hermelink, H. K., De Wolf-Peeters, C., Piccaluga, P. P., Pileri, S., Neri, A., & Inghirami, G. (2010). Gene expression profiling uncovers molecular classifiers for the recognition of anaplastic large-cell lymphoma within peripheral T-cell neoplasms. Journal of Clinical Oncology, 28(9), 1583-1590. https://doi.org/10.1200/JCO.2008.20.9759