Identification of genes involved in resistance to interferon-alpha in cutaneous T-cell lymphoma.
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
L
Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
Villuendas
Raquel
R
Ortiz
Pablo
P
Dopazo
Ana
A
Spiteri
Inmaculada
I
Lombardia
Luis
L
Rodríguez-Peralto
Jose L
JL
Fernández-Herrera
Jesús
J
Hernández
Almudena
A
Fraga
Javier
J
Dominguez
Orlando
O
Herrero
Javier
J
Alonso
Miguel A
MA
Dopazo
Joaquin
J
Piris
Miguel A
MA
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D007700:Kinetics; D016410:Lymphoma, T-Cell, Cutaneous / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008562:Membrane Glycoproteins; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D017472:Receptors, Interleukin-1; D015203:Reproducibility of Results; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D012334:RNA, Neoplasm; D017472:Receptors, Interleukin-1; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C434984:TIRAP protein, human; D015534:Trans-Activators