Isoform-Specific Functions of p73 Drive Survival and Chemoresistance in Diffuse Large B-Cell Lymphoma

Abstract

Diffuse large B-cell lymphoma (DLBCL) represents 30-40% of non-Hodgkin lymphoma cases and is curable in >60% of patients; however, approximately one-third ultimately relapse. Although prior studies in normal B cells and lymphoma models implicate p73 in B-cell lymphomagenesis, the functional role of individual p73 isoforms in DLBCL remains poorly defined. TP73, a TP53 family member located on chromosome 1p36, encodes both transcriptionally active (TAp73) and dominant-negative ({Delta}Np73) isoforms that differentially regulate apoptosis and proliferation. In this study, we characterized p73 locus alterations, isoform-specific expression patterns, and their biological relevance in DLBCL. Chromosomal analysis revealed disruption of the 1p36 locus--predominantly via heterozygous deletion--in 35% of patient samples, which significantly correlated with elevated {Delta}Np73 expression. Immunohistochemical profiling demonstrated a positive association between TAp73 and cleaved caspase-3, and between {Delta}Np73 and Ki-67. Conversely, TAp73 expression negatively correlated with the anti-apoptotic proteins Bcl-2 and Bcl-6. Functional studies in DLBCL cell lines further confirmed that TAp73 enhances sensitivity to serum deprivation and doxorubicin, whereas {Delta}Np73 overexpression promotes survival and chemoresistance. Together, these findings identify p73 isoform imbalance as a key contributor to DLBCL pathogenesis and therapeutic response, highlighting {Delta}Np73 as a potential biomarker of aggressive disease and treatment resistance, and TAp73 as a tumor-suppressive axis warranting further investigation. SummaryDiffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma, yet relapse remains a major challenge. The p73 gene produces two key isoforms with opposing functions: TAp73, which promotes apoptosis, and {Delta}Np73, which inhibits cell death and supports tumor growth. In DLBCL samples, 1p36 chromosomal disruption occurred in 35% of cases and was associated with elevated {Delta}Np73. TAp73 expression correlated with apoptosis markers, whereas {Delta}Np73 correlated with proliferation. Functional studies showed TAp73 sensitizes DLBCL cells to stress and chemotherapy, while {Delta}Np73 enhances resistance. These findings highlight {Delta}Np73 as a potential biomarker and therapeutic target in DLBCL.