Gene Expression Analysis of Peripheral T-Cell Lymphoma Not Otherwise Specified Reveals the Existance of Two Subgroups Related to Different Cellular Counterparts and Recurrent PDGFRA Deregulation.

Peripheral T-cell lymphoma not otherwise specified (PTCL/NOS) is a rare non Hodgkin lymphoma characterized by heterogeneous morphologic and phenotypic features, aggressive clinical behavior, poor response to conventional treatments and dismal prognosis. Its molecular basis and relationships to normal T-cells are still unclear. We performed gene expression profiling of 17 PTCL/NOS cases, collected at diagnosis before any treatment, and 20 samples of normal T-lymphocytes. The comparison of the gene expression profiles of PTCL/NOS and purified normal T-cell subpopulations, including CD4⁺, CD8⁺, resting (HLA-DR^-), and activated (HLA-DR⁺) elements, shows that PTCLs/NOS are more related to activated peripheral T-lymphocytes either CD4+ or CD8+, suggesting derivation from these compartments. Notably, immunohistochemistry on routine sections by using anti-CD4 and CD8 antibodies does not vicariate molecular analysis, as there is no correspondence between the global gene expression profile and CD4/CD8 antigen positivity. When compared with normal T-cells, PTCLs/NOS displayed a remarkable deregulation of functional programs often involved in tumorigenesis, such as apoptosis, proliferation, cell adhesion, and matrix remodeling. In addition, our analyses identified several genes that are specifically expressed in PTCLs/NOS. Their expression was confirmed at the protein level by immunohistochemical analysis of tissue micro-arrays including 160 primary PTCL/NOS cases. We applied several different markers that provided significant information as concerns the ectopic, paraphysiologic or stromal expression of the proteins corresponding to the deregulated genes. Among others, PTCLs/NOS aberrantly express CYR61, a molecule involved in drug resistance, and PDGFRA, a tyrosine kinase receptor whose deregulation is often related to a malignant phenotype. Notably, we demonstrated the constitutive activation of PDGFRA in the majority of cases - as indicated by its phosphorylation. Finally, we showed that imatinib mesylate significantly reduces PTCL/NOS primary cells viability after in vitro exposure at 1 mM concentration, independently from their sensitivity to conventional cytotoxic agents. These results are provided with biological implications relevant to the pathogenesis of the tumor, as well as for its clinical management.