Inverse Relationship Between the Transcription Repressor Yin Yang 1 (YY1) and the TRAIL Death Receptor DR5 in AIDS-Related Non-Hodgkin's Lymphoma Tissues: Potential Prognostic Biomarkers and Targets for Therapeutic Intervention.

Abstract 1932

Poster Board I-955

Patients infected with HIV develop AIDS-related Non-Hodgkin's lymphoma (ARL). The onset and pathogenesis of ARL has been the subject of many studies and several mechanisms have been proposed including immunosuppression (severe CD4 depletion), association with EBV infection, chronic antigenic stimulation and cytokine overproduction. The host immune system (both innate and adaptive) has been invoked in the immune surveillance against neoplastic transformation through various cytotoxic mechanisms. Cytotoxic cells such as NK and CTL mediate their cytotoxic functions via the perforin/granzyne and TNF family ligands. Escape from cytotoxic-mediated immune surveillance mechanisms by resistant onset of ARL will result in the proliferation and development of malignant ARL. We have reported that ARL cell lines are resistant to TNF family ligands such as FasL and TRAIL and the resistance can be reversed through various sensitizing agents. For instance, resistance to both FasL and TRAIL were shown to be due, in large part, to tumor cells over expressing the Fas and DR5 transcription repressor Yin Yang 1 (YY1). YY1 overexpression in tumor cells inhibits the transcription of Fas and DR5 through its YY1 direct DNA-binding activity on the respective promoters. The direct inhibition of YY1 activity/expression results in the upregulation of Fas and DR5 and reversal of resistance to the respective ligands. Thus, we hypothesized that ARL may over express YY1 through hyper activation of upstream constitutively activated NF-ĸB and resulting in the downregulation of Fas and DR5 and, hence, resistance to FasL and TRAIL-mediated apoptosis. Such manifestations will contribute to the pathogenesis and growth of ARL. We have examined the expression of YY1 and DR5 in large numbers of patient-derived ARL tissues using tissue microarrays obtained from the AIDS and Cancer Speciments Resource (ACSR). Analysis of the arrays for density expression revealed that YY1 was significantly over expressed, compared to normal or adjacent tissue, and DR5 was significantly repressed. Further analysis of the arrays revealed that there exists several subsets with differential expression namely (1) a subset (n= 21) where there was low detectable DR5 and high expression of YY1 (2) a subset (n=7) with medium DR5 expression and medium YY1 expression and (3) a subset (n= 5) very high DR5 expression and low YY1. In all 3 subsets, the inverse relationship between YY1 and DR5 was maintained. These data demonstrate that patients-derived ARL over express YY1 and under express DR5 and these two biomarkers may be of prognostic significance and targets for therapeutic intervention once validated in a larger cohort of specimens. (This work was support by Fogarty program and Terry Fox Foundation)