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

TitleGene expression profiling uncovers molecular classifiers for the recognition of anaplastic large-cell lymphoma within peripheral T-cell neoplasms.
Publication TypeJournal Article
Year of Publication2010
AuthorsPiva 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 HKonrad, De Wolf-Peeters C, Piccaluga PPaolo, Pileri S, Neri A, Inghirami G
JournalJ Clin Oncol
Date Published2010 Mar 20
KeywordsAnaplastic Lymphoma Kinase, Biomarkers, Tumor, Cell Line, Tumor, Cell Transformation, Neoplastic, Gene Expression Profiling, Humans, Lymphoma, Large-Cell, Anaplastic, Lymphoma, T-Cell, Peripheral, Nuclear Proteins, Protein-Tyrosine Kinases, Receptor Protein-Tyrosine Kinases, Signal Transduction

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.

Alternate JournalJ Clin Oncol
PubMed ID20159827
Related Faculty: 
Giorgio Inghirami, M.D.

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