Therapeutic implications of intratumor heterogeneity for TP53mutational status in Burkitt lymphoma

Enrico Derenzini, Ilaria Iacobucci, Claudio Agostinelli, Enrica Imbrogno, Clelia Tiziana Storlazzi, Alberto L`Abbate, Beatrice Casadei,Anna Ferrari, Andrea Ghelli Luserna Di Rora`, Giovanni Martinelli, Stefano Pileri and Pier Luigi Zinzani

Experimental Hematology & Oncology20154:24

DOI: 10.1186/s40164-015-0019-9

Received: 3 July 2015

Accepted: 4 August 2015

Published: 27 August 2015

Abstract

Therapeutic implications of intra-tumor heterogeneity are still undefined. In this study we report a genetic and functional analysis aimed at defining the mechanisms of chemoresistance in a 43-year old woman affected by stage IVB Burkitt lymphoma with bulky abdominal masses and peritoneal effusion. The patient, despite a transient initial response to chemotherapy with reduction of the bulky masses, rapidly progressed and died of her disease. Targeted TP53 sequencing found that the bulky mass was wild-type whereas peritoneal fluid cells harbored a R282W mutation. Functional studies onTP53 mutant cells demonstrated an impaired p53-mediated response, resistance to ex vivo doxorubicin administration, overexpression of DNA damage response (DDR) activation markers and high sensitivity to pharmacologic DDR inhibition. These findings suggest that intra-tumor heterogeneity for TP53 mutational status may occur in MYC-driven cancers, and that DDR inhibitors could be effective in targeting hidden TP53 mutant clones in tumors characterized by genomic instability and prone to intra-tumor heterogeneity.