Abstract
Abstract Abnormalities of chromosome 1p36 locus are frequently detected in non Hodgkin lymphoma (NHL) and are associated with aggressive clinical behavior. TP73, a gene at 1p36 locus, is a member of the p53 tumor suppressor gene family, and regulates many important cellular pathways. TP73 gene function is controlled by a balance between two isoforms with opposing functions, the full length TAp73 protein (pro-apoptotic) and the NH2-terminally truncated ΔNp73 protein (anti-apoptotic through antagonizing both TAp73 and p53). Our previous work on diagnostic specimens of NHL cases had shown a differential ΔNp73 up-regulation and increase in ΔNp73:TAp73 expression ratio among NHL cases with 1p36 chromosomal disruption as compared to NHL cases without 1p36 disruption, which correlates with decreased apoptosis, increased cellular proliferation and increased angiogenesis. We hypothesized that modulated expression of the p73 isoforms will alter the aggressive behavior of a NHL cell line containing 1p36 disruption. We used a NHL cell line (Granta-519) that has 1p36 disruption as a model. Granta-519 cells express higher levels of ΔNp73 isoform similar to what was observed in NHL cases with 1p36 abnormality. Next, we stably transfected Granta-519 with a TAp73 mammalian expression vector to modulate the ΔNp73:TAp73 ratio. Cell cycle analysis showed an increase in the percentage of G1 cells and decrease in the percentage of S and G2 cells in TAp73-trasnfected Granta-519 cells as compared to control vector-transfected cells. Serum deprivation significantly inhibited the growth of Granta-519-TAp73- cells as compared to control vector-transfected cells. Moreover, reconstitution of TAp73 expression in Granta-519 cells significantly enhanced their response to Doxorubicin. Together, these results provide an insight on modulation of ΔNp73:TAp73 as a novel therapeutic target in NHL with 1p36 abnormalities. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1180. doi:1538-7445.AM2012-1180
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