The function of PUMA (p53-upregu-lated mediator of apoptosis, also known as BBC3) in tumorigenesis has been the subject of some debate. A recent study has added to this by showing that Puma loss can cooperate with MYC to accelerate tumour development in a murine model of Burkitt lymphoma (BL).

Transgenic mice expressing Eµ-Myc develop fully penetrant B-cell lymphomas that closely resemble human BL. Cells from these mice have been used to show that p53-dependent apoptosis is a rate-limiting step for lymphomagenesis. Consequently, the p53 pathway is compromised in the majority of murine and human lymphomas. Zambetti and colleagues generated Eµ-Myc;Puma–/– mice and found that Puma deficiency accelerated the onset of tumour development, strongly suggesting a role for Puma in limiting lymphomagenesis. To further explore this possibility and to examine the role of PUMA in the premalignant stages of the disease, apoptosis levels were measured in primary B cells from Eµ-Myc and Eµ-Myc;Puma–/– mice. Notably, Puma loss reduced apoptosis to levels comparable with those found in non-transgenic mice, suggesting that PUMA-mediated apoptosis is a serious hurdle for an Eµ-Myc B cell with malignant aspirations.

Given the importance of PUMA in p53-dependent apoptosis, the authors predicted that Puma deficiency would negate the require-ment for further mutations in the

p53 pathway. Surprisingly, however, both Cdkn2d (which encodes ARF) and Trp53 mutations were observed in Puma-null lymphomas, implying that Puma loss is not sufficient to overcome the requirement to disable the p53 pathway. Nevertheless, PUMA expression was markedly down-regulated in the majority of established Eµ-Myc lymphomas and primary lymphoma samples from patients with BL. PUMA has a high CpG dinucleotide content, so the authors investigated whether promoter methylation was responsible for the reduction in PUMA expression. Tellingly, half of the BL samples with undetectable PUMA mRNA levels showed significant DNA and histone methylation. Moreover, human BL cell lines that have a methylated PUMA promoter displayed robust

upregulation of PUMA mRNA and protein and subsequent induction of apoptosis when treated with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine.

DNA methyltransferase inhibitors are currently being tested in clinical trials for the treatment of human cancers, and the authors hypothesize using such agents to restore PUMA function in patients with BL might be a useful therapeutic strategy. However, as the authors also found that mutations within the p53 pathway are still selected for in the absence of PUMA, the debate on the function of PUMA in the p53 pathway and in tumorigenesis will continue.

Safia Ali Danovi

t u m o r i g e n e s i s

PUMA strikes again

originAL reseArCH PAPer Garrison, S. P. et al. Selection against PUMA gene expression in Myc-driven B cell lymphomagenesis. Mol. Cell. Biol. 45, 23 Jun 2008 (doi 10.1128/MCB.00907-07)

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NATURe ReviewS | cancer voLUMe 8 | AUGUST 2008

Nature Reviews Cancer | AoP, published online 10 July 2008; doi:10.1038/nrc2449

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