Abstract
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma (NHL) and is curable in more than 60% of the cases. Despite long-term remission achieved with current therapies, relapse occurs in almost one-third of the cases. Rearrangements of chromosome locus 1p36 with ensuing deletion or disruption of TP73, one of the most distally located putative tumor suppressor genes, is frequent in many NHL subtypes, including DLBCL, and confers inferior prognosis. Recent 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 DLBCL is not clear. TP73 is a member of the TP53 family that shares structural homology and hence is capable of transactivating p53 target genes. We investigated the relationship between rearrangements of chromosome locus 1p36 and p73 expression and examined whether differential expression of p73 isoforms (TAp73 and ΔNp73) correlate with proliferation and apoptosis in DLBCL. We utilized molecular techniques in conjunction with fluorescence in situ hybridization (FISH) in untreated histologically confirmed DLBCL patient specimens. In our data set, the 1p36 chromosomal locus was disrupted (mainly heterozygous deletion) in 35% of the cases and was significantly associated with ΔNp73 expression. Subsequent immunohistochemical analysis showed a significant positive correlation between TAp73 and cleaved caspase-3 expression and between ΔNp73 and Ki-67 expression. Additionally, we observed a negative correlation between TAp73 and the anti-apoptotic molecules Bcl-2 and Bcl-6. We then performed in vitro studies in DLBCL cells and modulated the expression of TAp73 and ΔNp73 using expression vectors and siRNA. TAp73-transfected cells were more susceptible to serum deprivation and doxorubicin treatment, conversely the ΔNp73-transfected cells were more resistant to serum deprivation and doxorubicin treatment compared to control cells. Thus, rearrangements of 1p36 consequently deregulates p73 isoform expression in DLBCL. Our data emphasizes the importance of delineating the functional aspect of genetic alterations and underscores the significant role of p73 isoforms in DLBCL pathogenesis and treatment.
Citation Format: Hesham M. Hassan, Michelle L. Varney, Pamela A. Althof, Gabriel C. Caponetti, Kai Fu, Dennis D. Weisenburger, Rakesh K. Singh, Bhavana J. Dave. P73 isoforms regulate cellular survival and response to treatment in diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2157. doi:10.1158/1538-7445.AM2017-2157