Biological Differences in Peripheral T-Cell Lymphomas Identified by DNA Microarrays.

Peripheral T-cell lymphomas (PTCL) constitute a heterogeneous and aggressive group of tumors whose pathogenic alterations remain largely unknown. They show great morphologic, immunophenotypic and clinical differences. Expression profiling has been demonstrated to be a useful tool for the molecular classification of tumours. We used DNA microarrays (Affymetrics, Lymph_DX) to look for molecular differences in peripheral T-cell lymphomas.

We analysed the expression of 19 pathologically confirmed PTCL (11 PTCL, unspecified (u) and 8 angioimmunoblastic, AILT). A time-course of stimulation with anti-CD3 and anti-CD28 was performed in CD4+ and CD8+ isolated peripheral blood lymphocytes, and the gene expression of tumors was compared with resting and stimulated normal T-cells. Cases of classical Hodgkin’s lymphoma, with which PTCL may be confused, were included.

Gene expression of PTCL revealed several clusters of genes with biological significance showing differential expression within the tumors. We defined a “Cytotoxic Response” cluster characterized by the expression of cytotoxic molecules PRF1 and GZMB and GZMH, a “B-cell-related genes” cluster which included B-cell specific genes PAX5 or CD19, and an interesting “Resting-cells genes” cluster. These three clusters were negatively correlated with a “Proliferation” signature. On the other hand, the “Proliferation” signature significantly correlated with the expression of TNFRSF8 (CD30) (r=0.63, p=0.003) and the expression of CD3G (r=0.51, p=0.022). Other interesting genes were also found associated specifically to the proliferation of PTCL.

Comparison between PTCLu and AILT showed differences in the expression of CD21 and other genes reflecting the higher presence of dendritic cells in AILT, and also revealed differences in expression of relevant chemokines, such us CXCL5, CXCL13 and CCL19.

Intriguingly, compared with normal CD4 and CD8 T-cells, PTCL showed lower expression of most of the typical genes associated with T-cell biology, suggesting that PTCL often lose the common genetic program of T-cells. PTCL expression profiles are difficult to interpret due to the significant proportion of other infiltrating cells accompanying the tumor. Our results showed that microarrays are a helpful tool to dissect the PTCL expression profile, identifying those genes expressed by infiltrating cells and those expressed by tumor cells.