RESUMEN
Two distinct primary cutaneous large B cell lymphomas are recognized: primary cutaneous follicle centre lymphoma (PCFCL), characterized by an excellent prognosis, and primary cutaneous large B cell lymphoma, leg-type (PCLBCL leg-type), with an unfavourable prognosis. To determine whether inhibition of the apoptosis pathways may underlie the difference in clinical outcome between PCFCL and PCLBCL leg-type, we investigated the expression of only apoptosis-related genes by microarray expression profiling. Unsupervised cluster analysis was carried out using 169 genes involved in apoptosis on a group of 21 previously untreated patients diagnosed with primary cutaneous large B cell lymphoma. Cluster analysis resulted in two separate groups which showed large overlap with the PCFCL and PCLBCL leg-type. One group was characterized by high expression levels of pro- and anti-apoptotic genes. The other group was characterized by high expression levels of apoptosis-inducing cytotoxic effector genes, possibly reflecting a cellular cytotoxic immune response. Our results suggest that the clinically favourable PCFCLs are characterized by a relatively intense cellular cytotoxic immune response and that PCLBCL leg-types are characterized by constitutive activation of the intrinsic mediated apoptosis pathway, with concomitant downstream inhibition of this apoptosis pathway. Thus, strategies neutralizing the function of apoptosis-inhibiting proteins might be effective in PCLBCL leg-type.
Asunto(s)
Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Linfoma de Células B Grandes Difuso/genética , Neoplasias Primarias Múltiples/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Cutáneas/genética , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/genética , Análisis por Conglomerados , Citotoxicidad Inmunológica/genética , Femenino , Humanos , Inmunohistoquímica , Pierna , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Cuero Cabelludo , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/mortalidad , Análisis de Supervivencia , TóraxRESUMEN
AIMS: Tumour necrosis factor (TNF)-receptor associated factor 2 (TRAF2) is an adaptor molecule involved in nuclear factor (NF)-kappaB activation, which is characteristic of in vitro activated B-cell (ABC)-like diffuse large B-cell lymphomas (DLBCL) and may result in expression of anti-apoptotic genes and poor response to chemotherapy. TRAF2 also has direct anti-apoptotic properties via interference with the apoptosis signalling cascade. The aim was to determine whether TRAF2 is preferentially expressed in ABC-like DLBCL, and whether expression correlates with clinical outcome. METHODS AND RESULTS: TRAF2 was expressed in nine of 20 tested ABC-like DLBCLs and in only one of 13 tested germinal centre B-lymphocyte (GCB)-like DLBCLs. High TRAF2 expression was correlated with high International Prognostic Index at time of presentation, high chance of relapse and short progression-free survival time in 44 tested DLBCLs. Furthermore, when analysis was restricted to ABC-like DLBCL only, TRAF2 expression was significantly associated with poor progression-free survival time. CONCLUSIONS: TRAF2 might be involved in activation of NF-kappaB in a subset of ABC-like DLBCL, and its expression is associated with a particularly poor outcome in primary nodal DLBCL patients. Because of its possible effect on to chemotherapy resistance, resistance, TRAF2 might be an attractive candidate as a molecular target for TRAF2+ DLBCL.
