TP73 in Non-Hodgkin lymphoma pathogenesis and therapy

Secondary chromosomal rearrangements play an important role in the progression and prognosis of Non-Hodgkin lymphoma (NHL) with frequent rearrangement of the chromosome 1p36 locus. The TP73 gene as one of the most distally located candidate genes at this locus is likely to be deleted or disrupted. Additionally, TP73 shares homology to TP53 and is capable of transactivating p53 target genes. We analyzed the relationship between 1p36 and p73 and whether p73 is involved in the regulation of proliferation and survival in common subtypes of NHL. In both follicular (FL) and diffuse large B cell lymphoma (DLBCL), there was an association between 1p36 chromosomal rearrangement and deregulated p73 isoform expression and a correlation between differential p73 isoform expression and proliferation and apoptosis. Subsequently, we modulated the expression of the two opposing p73 isoforms (TAp73 and ANp73) using expression vectors and siRNA which resulted in altered growth, and response to serum deprivation and chemotherapy in DLBCL cells. Despite improvement in NHL outcome, recurrence and residual disease are ongoing problems. Diclofenac is a NSAID that was found to modulate p73 isoform expression and inhibit the growth of neuroblastoma. Based on our observation of the regulation of apoptosis and therapeutic response of NHL cells by p73, we investigated the effect of diclofenac on the behavior of two clinically aggressive NHL subtypes, DLBCL and mantle cell lymphoma (MCL). Diclofenac treatment of DLBCL or MCL cell lines resulted in dose- and duration-dependent growth inhibition independent of p53 status. Biological studies showed evidence of profound cell death and cell cycle arrest. Molecular studies demonstrated caspase cascade activation and modulation of p73 isoforms in favor of apoptosis, and induction of p53 family pro-apoptotic and cell cycle regulatory targets independent of p53 status. In summary, studies performed in this project provide a possible molecular explanation for the prognostic effect of 1 p36 chromosomal rearrangement, p73 as a possible therapeutic target, and the potential of diclofenac as a novel adjuvant therapeutic agent in NHL management.