Abstract
Abstract
Rearrangements of the chromosome locus 1p36 with ensuing deletion or disruption of TP73, one of the most distally located putative tumor suppressor genes, is frequent in non-Hodgkin lymphoma (NHL) and confers inferior prognosis. TP73 shares homology to TP53 and is capable of transactivating p53 target genes. Earlier reports in normal B-cells and lymphoma animal models suggest an important role of p73 in B-cell lymphomas, however, the biological significance of p73 isoforms in Diffuse large B-cell lymphoma (DLBCL) is not clear. Diffuse large B-cell lymphoma is the most common form of NHL, and although long-term remission is achieved with current therapies, relapse occurs in almost one-third of the patients. Previously, we have demonstrated that the differential expression of p73 isoforms (TAp73 and ΔNp73) correlate with proliferation and apoptosis in DLBCL. In the present study, we examined whether modulating the expression of these p73 isoforms in DLBCL cells regulates cell survival, proliferation, and response to the chemotherapeutic agent, doxorubicin. We performed in vitro studies in DLBCL cells and modulated the expression of the two opposing p73 isoforms (TAp73 and ΔNp73) using expression vectors and siRNA in DHL16 (GCB subtype) and OCI-Ly3 (ABC subtype) cells. Under normal conditions TAp73-transfected cells showed comparable growth to control vector-transfected cells; however, the TAp73-transfected cells were more susceptible to serum deprivation as well as doxorubicin. In contrast, ΔNp73-transfected cells had accelerated growth when compared with control vector-transfected cells under normal conditions and were more resistant to serum deprivation and doxorubicin treatment. Subsequently, we analyzed the p73 direct transcriptional pro-apoptotic targets in cells transfected with TAp73 and ΔNp73 and vector control. Both the common p53 and p73 targets (PUMA and NOXA) as well as the exclusively p73 targetsGRAMD4 and BIM, were up-regulated in the TAp73-transfected cells compared to control cells. A reduction of PUMA, BIM, and GRAMD4 was observed in the ΔNp73-transfected cells as compared to control cells. Furthermore, we observed that p73 knockdown using p73 siRNA altered the growth and the response to doxorubicin in both DLBCL cell lines. Together, these data demonstrate the significant biological role of p73 isoforms in DLBCL pathogenesis and therapeutic response. Our findings illustrate that modulation of TP73 isoforms induces apoptosis and expression of pro-apoptotic targets, thus establishing p73 as a potential therapeutic target in DLBCL.
Citation Format: Hesham M. Hassan, Michelle L. Varney, Sugandha Saxena, Rakesh K. Singh, Bhavana J. Dave. Differential expression of TP73 isoforms modulates cell survival and therapeutic response in diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2055.