Maximal killing of lymphoma cells by DNA damage-inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim

Happo, Lina, Cragg, Mark.S., Phipson, Belinda, Haga, Jon M., Jansen, Elisa S., Herold, Marco J., Dewson, Grant, Michalak, Ewa M., Vandenberg, Cassandra J., Smyth, Gordon K., Strasser, Andreas, Cory, Suzanne and Scott, Clare L. (2010) Maximal killing of lymphoma cells by DNA damage-inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim. Blood, 116 (24), 5256-67. (doi:10.1182/blood-2010-04-280818). (PMID:20829369)

Abstract

DNA-damaging chemotherapy is the backbone of cancer treatment, although it is not clear how such treatments kill tumor cells. In nontransformed lymphoid cells, the combined loss of 2 proapoptotic p53 target genes, Puma and Noxa, induces as much resistance to DNA damage as loss of p53 itself. In E?-Myc lymphomas, however, lack of both Puma and Noxa resulted in no greater drug resistance than lack of Puma alone. A third B-cell lymphoma-2 homology domain (BH)3-only gene, Bim, although not a direct p53 target, was up-regulated in E?-Myc lymphomas incurring DNA damage, and knockdown of Bim levels markedly increased the drug resistance of E?-Myc/Puma?/?Noxa?/? lymphomas both in vitro and in vivo. Remarkably, c-MYC–driven lymphoma cell lines from Noxa?/?Puma?/?Bim?/? mice were as resistant as those lacking p53. Thus, the combinatorial action of Puma, Noxa, and Bim is critical for optimal apoptotic responses of lymphoma cells to 2 commonly used DNA-damaging chemotherapeutic agents, identifying Bim as an additional biomarker for treatment outcome in the clinic.

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Contributors

Author: Mark.S. Cragg

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