Identification of genes involved in resistance to interferon-alpha in cutaneous T-cell lymphoma

TitleIdentification of genes involved in resistance to interferon-alpha in cutaneous T-cell lymphoma
Publication TypeJournal Article
Year of Publication2002
AuthorsTracey, L, Villuendas, R, Ortiz, P, Dopazo, A, Spiteri, I, Lombardia, L, Rodriguez-Peralto, JL, Fernandez-Herrera, J, Hernandez, A, Fraga, J, Dominguez, O, Herrero, J, Alonso, MA, Dopazo, J, Piris, MA
JournalAm J Pathol
KeywordsAntineoplastic Agents/*pharmacology/therapeutic use Carrier Proteins/biosynthesis/genetics DNA-Binding Proteins/biosynthesis/genetics Drug Resistance; Biological Oligonucleotide Array Sequence Analysis RNA; Cultured; Cutaneous/diagnosis/drug therapy/*genetics/metabolism *Membrane Glycoproteins Models; Interleukin-1 Reproducibility of Results STAT1 Transcription Factor STAT3 Transcription Factor Trans-Activators/biosynthesis/genetics Tumor Cells; Neoplasm Gene Expression Profiling *Gene Expression Regulation; Neoplasm/biosynthesis *Receptors; Neoplastic Humans Interferon-alpha/*pharmacology/therapeutic use Kinetics Lymphoma; T-Cell

Interferon-alpha therapy has been shown to be active in the treatment of mycosis fungoides although the individual response to this therapy is unpredictable and dependent on essentially unknown factors. In an effort to better understand the molecular mechanisms of interferon-alpha resistance we have developed an interferon-alpha resistant variant from a sensitive cutaneous T-cell lymphoma cell line. We have performed expression analysis to detect genes differentially expressed between both variants using a cDNA microarray including 6386 cancer-implicated genes. The experiments showed that resistance to interferon-alpha is consistently associated with changes in the expression of a set of 39 genes, involved in signal transduction, apoptosis, transcription regulation, and cell growth. Additional studies performed confirm that STAT1 and STAT3 expression and interferon-alpha induction and activation are not altered between both variants. The gene MAL, highly overexpressed by resistant cells, was also found to be expressed by tumoral cells in a series of cutaneous T-cell lymphoma patients treated with interferon-alpha and/or photochemotherapy. MAL expression was associated with longer time to complete remission. Time-course experiments of the sensitive and resistant cells showed a differential expression of a subset of genes involved in interferon-response (1 to 4 hours), cell growth and apoptosis (24 to 48 hours.), and signal transduction.


Tracey, Lorraine Villuendas, Raquel Ortiz, Pablo Dopazo, Ana Spiteri, Inmaculada Lombardia, Luis Rodriguez-Peralto, Jose L Fernandez-Herrera, Jesus Hernandez, Almudena Fraga, Javier Dominguez, Orlando Herrero, Javier Alonso, Miguel A Dopazo, Joaquin Piris, Miguel A Research Support, Non-U.S. Gov’t United States The American journal of pathology Am J Pathol. 2002 Nov;161(5):1825-37.