p53 status dictates responses of B lymphomas to monotherapy with proteasome inhibitors.
The proapoptotic function of p53 is thought to underlie most anticancer modalities and is also activated in response to oncogenic insults, such as overexpression of the Myc oncoprotein. Here we generated tractable B lymphomas using retroviral transduction of the MYC oncogene into hematopoietic cells with 2 knock-in alleles encoding a fusion between p53 and 4-hydroxytamoxifen (4OHT) receptor (p53ER(TAM)). In these polyclonal tumors, Myc is the only oncogenic lesion, and p53ER(TAM) status can be rapidly toggled between "off" and "on" with 4OHT, provided that the Trp53 promoter has been independently activated. Although 4OHT can trigger widespread apoptosis and overt tumor regression even in the absence of DNA-damaging agents, in tumors with high levels of Mdm2 these responses are blunted. However, cotreatment with proteasome inhibitors fully restores therapeutic effects in vivo. Similarly, human Burkitt lymphomas with wild-type p53 and overexpression of Hdm2 are highly sensitive to proteasome inhibitors, unless p53 levels are reduced using the HPV-E6 ubiquitin ligase. Therefore, proteasome inhibitors could be highly effective as a monotherapy against Myc-induced lymphomas, with no need for adjuvant chemotherapy or radiation therapy. On the other hand, their efficacy is crucially dependent on the wild-type p53 status of the tumor, placing important restrictions on patient selection.
Yu
Duonan
D
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104, USA.
Carroll
Martin
M
Thomas-Tikhonenko
Andrei
A
D000483:Alleles; D000818:Animals; D004965:Estrogen Antagonists / Q000494:pharmacology; D016158:Genes, p53; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D004965:Estrogen Antagonists; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; C016601:afimoxifene; D051736:Proto-Oncogene Proteins c-mdm2