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 (ΔNp73) 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 ΔNp73 expression. Immunohistochemical profiling demonstrated a positive association between TAp73 and cleaved caspase-3, and between ΔNp73 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 ΔNp73 overexpression promotes survival and chemoresistance. Together, these findings identify p73 isoform imbalance as a key contributor to DLBCL pathogenesis and therapeutic response, highlighting ΔNp73 as a potential biomarker of aggressive disease and treatment resistance, and TAp73 as a tumor-suppressive axis warranting further investigation. Summary Diffuse 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 ΔNp73, which inhibits cell death and supports tumor growth. In DLBCL samples, 1p36 chromosomal disruption occurred in 35% of cases and was associated with elevated ΔNp73. TAp73 expression correlated with apoptosis markers, whereas ΔNp73 correlated with proliferation. Functional studies showed TAp73 sensitizes DLBCL cells to stress and chemotherapy, while ΔNp73 enhances resistance. These findings highlight ΔNp73 as a potential biomarker and therapeutic target in DLBCL. Competing Interest Statement The authors have declared no competing interest. Footnotes The funding information was updated. Thanks Data Availability Statement The data presented in this study are available in the article or supplementary material published.