Hassan, H.; Varney, M. L.; Weisenburger, D. D.; Singh, R. K.; Dave, B. J.

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 (deltaNp73) 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 deltaNp73 expression. Immunohistochemical profiling demonstrated a positive association between TAp73 and cleaved caspase-3, and between deltaNp73 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 deltaNp73 overexpression promotes survival and chemoresistance. Together, these findings identify p73 isoform imbalance as a key contributor to DLBCL pathogenesis and therapeutic response, highlighting deltaNp73 as a potential biomarker of aggressive disease and treatment resistance, and TAp73 as a tumor-suppressive axis warranting further investigation.