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Blood, 1 June 2007, Vol. 109, No. 11, pp. 4936-4943. Prepublished online as a Blood First Edition Paper on February 6, 2007; DOI 10.1182/blood-2006-10-050294. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-10-050294v1 109/11/4936    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Yu, D. Articles by Thomas-Tikhonenko, A. Search for Related Content PubMed PubMed Citation Articles by Yu, D. Articles by Thomas-Tikhonenko, A. Related Collections Neoplasia Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA p53 status dictates responses of B lymphomas to monotherapy with proteasome inhibitors Duonan Yu1, Martin Carroll2, and Andrei Thomas-Tikhonenko1 1 Department of Pathobiology, School of Veterinary Medicine, and 2 Division of Hematology-Oncology, School of Medicine, University of Pennsylvania, Philadelphia 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 (p53ERTAM). In these polyclonal tumors, Myc is the only oncogenic lesion, and p53ERTAM 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. A. Nikiforov, M. Riblett, W.-H. Tang, V. Gratchouck, D. Zhuang, Y. Fernandez, M. Verhaegen, S. Varambally, A. M. Chinnaiyan, A. J. Jakubowiak, et al. Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition PNAS, December 4, 2007; 104(49): 19488 - 19493. [Abstract] [Full Text] [PDF]

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