PUMA strikes again | Nature Reviews Cancer

Access through your institution Buy or subscribe 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

_E_μ_-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

requirement 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

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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) Download

references Authors * Safia Ali Danovi View author publications You can also search for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE

CITE THIS ARTICLE Danovi, S. PUMA strikes again. _Nat Rev Cancer_ 8, 569 (2008). https://doi.org/10.1038/nrc2449 Download citation * Published: 10 July 2008 * Issue Date: August 2008 * DOI:

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