HIV infection is associated with an increased risk of Non-Hodgkin’s B cell lymphoma (AIDS-NHL). AIDS-NHL may arise, in part, because the patients may be immunocompromised and tumor escape takes place. The standard treatment for NHL is chemotherapy, however, many patients become refractory to such treatments. Alternative treatment modalities include immunotherapy, though, even in the presence of an effective anti-tumor response, the tumor may develop mechanisms of resistance to immune-mediated cytotoxicity (e.g., Fas-ligand, TRAIL) and resistance to apoptosis. We have shown that overexpression of the transcription factor Yin-Yang 1 (YY1) is involved in the regulation of tumor cell resistance to FasL-induced apoptosis. The direct role of YY1 was demonstrated in cells transfected with siRNA YY1 which were sensitized to Fas-induced apoptosis (Vega, et al., 2005, Journal of Immunology (In Press)). In addition, we have also shown that overexpression of YY1 and X-linked inhibitor of apoptosis (XIAP) regulate the resistance of tumor cells to TRAIL-induced apoptosis (
Ng and Bonavida, 2002, Molecular Cancer Therapeutics 1:1051–1058
, Huerta-Yepez, et al., 2004, Oncogene 23:4993–5003
). Hence, we hypothesized that one mechanism of AIDS-NHL immune escape may be due to overexpression of YY1 and XIAP. Tissue arrays containing formalin fixed, paraffin embedded sections from AIDS lymphoma were obtained from the AIDS and Cancer Specimen Resource (ACSR) of the National Cancer Institute (NCI). These arrays consisted of 21 Burkitt, 29 Large Cell Lymphoma, and 6 Small Cell Lymphoma. Immunohistochemistry was performed for the expression of YY1, and XIAP. The arrays were scored and both the percent of positive cells and the intensity were recorded and the data were analyzed statistically. The findings reveal that YY1 and XIAP were overexpressed in the majority of the AIDS-NHL patient specimens. In addition, there was a significant correlation between YY1 and XIAP expression in all 3 types of lymphoma. These studies and studies based on in vitro findings with AIDS-NHL cell lines suggest that overexpression of YY1 and XIAP may be involved in the pathogenesis of AIDS-NHL and are potential markers for tumor unresponsiveness to immune-mediated cytotoxic therapies. Furthermore, inhibitors of YY1 and XIAP expression/activity may be targets for therapeutic intervention when combined with immunotherapy.
