Therapeutic implications of intratumor heterogeneity for TP53 mutational 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, Pier Luigi Zinzani

Research output: Contribution to journalArticle

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 on TP53 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.

Original languageEnglish
Article number24
JournalExperimental Hematology and Oncology
Volume4
Issue number1
DOIs
Publication statusPublished - Aug 27 2015

Keywords

  • Burkitt lymphoma
  • CHK1
  • Genomic instability
  • Intra-tumor heterogeneity
  • MYC
  • γ-H2AX

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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  • Cite this

    Derenzini, E., Iacobucci, I., Agostinelli, C., Imbrogno, E., Storlazzi, C. T., L'Abbate, A., Casadei, B., Ferrari, A., Di Rora`, A. G. L., Martinelli, G., Pileri, S., & Zinzani, P. L. (2015). Therapeutic implications of intratumor heterogeneity for TP53 mutational status in Burkitt lymphoma. Experimental Hematology and Oncology, 4(1), [24]. https://doi.org/10.1186/s40164-015-0019-9