title: Therapeutic implications of intratumor heterogeneity for TP53 mutational status in Burkitt lymphoma.
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.
authors: Department of Experimental, Diagnostic and Specialty Medicine, DIMES, Institute of Hematology and Medical Oncology L.A. Seragnoli, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy.
authors: Enrico
authors: E
authors: Derenzini
authors: Department of Experimental, Diagnostic and Specialty Medicine, DIMES, Institute of Hematology and Medical Oncology L.A. Seragnoli, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy.
authors: Ilaria
authors: I
authors: Iacobucci
authors: Hematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine, DIMES, University of Bologna, Bologna, Italy.
authors: Claudio
authors: C
authors: Agostinelli
authors: Department of Experimental, Diagnostic and Specialty Medicine, DIMES, Institute of Hematology and Medical Oncology L.A. Seragnoli, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy.
authors: Enrica
authors: E
authors: Imbrogno
authors: Department of Biology, University of Bari "Aldo Moro", Bari, Italy.
authors: Clelia Tiziana
authors: CT
authors: Storlazzi
authors: Department of Biology, University of Bari "Aldo Moro", Bari, Italy.
authors: Alberto
authors: A
authors: L Abbate
authors: Department of Experimental, Diagnostic and Specialty Medicine, DIMES, Institute of Hematology and Medical Oncology L.A. Seragnoli, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy.
authors: Beatrice
authors: B
authors: Casadei
authors: Department of Experimental, Diagnostic and Specialty Medicine, DIMES, Institute of Hematology and Medical Oncology L.A. Seragnoli, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy.
authors: Anna
authors: A
authors: Ferrari
authors: Department of Experimental, Diagnostic and Specialty Medicine, DIMES, Institute of Hematology and Medical Oncology L.A. Seragnoli, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy.
authors: Andrea Ghelli Luserna
authors: AG
authors: Di Rora
authors: Department of Experimental, Diagnostic and Specialty Medicine, DIMES, Institute of Hematology and Medical Oncology L.A. Seragnoli, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy.
authors: Giovanni
authors: G
authors: Martinelli
authors: Hematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine, DIMES, University of Bologna, Bologna, Italy.
authors: Stefano
authors: S
authors: Pileri
authors: Department of Experimental, Diagnostic and Specialty Medicine, DIMES, Institute of Hematology and Medical Oncology L.A. Seragnoli, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy.
authors: Pier Luigi
authors: PL
authors: Zinzani
keywords: Burkitt lymphoma; CHK1; Genomic instability; Intra-tumor heterogeneity; MYC; γ-H2AX