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Molecular and Cellular Biology, September 2008, p. 5391-5402, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.00907-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Selection against PUMA Gene Expression in Myc-Driven B-Cell Lymphomagenesis ^,

Sean P. Garrison,¹ John R. Jeffers,¹ Chunying Yang,⁴ Jonas A. Nilsson,³ Mark A. Hall,⁴ Jerold E. Rehg,² Wen Yue,⁵ Jian Yu,⁵ Lin Zhang,⁵ Mihaela Onciu,² Jeffery T. Sample,^1, John L. Cleveland,⁴ and Gerard P. Zambetti^1*

Departments of Biochemistry,¹ Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105,² Department of Molecular Biology, Umeå University, SE-901 87 Umeå, Sweden,³ Department of Cancer Biology, The Scripps Research Institute—Florida, Jupiter, Florida 33458,⁴ Department of Pharmacology and Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania⁵

Received 22 May 2007/ Returned for modification 19 July 2007/ Accepted 12 June 2008

The p53 tumor suppressor pathway limits oncogenesis by inducing cell cycle arrest or apoptosis. A key p53 target gene is PUMA, which encodes a BH3-only proapoptotic protein. Here we demonstrate that Puma deletion in the Eµ-Myc mouse model of Burkitt lymphoma accelerates lymphomagenesis and that 75% of Eµ-Myc lymphomas naturally select against Puma protein expression. Furthermore, approximately 40% of primary human Burkitt lymphomas fail to express detectable levels of PUMA and in some tumors this is associated with DNA methylation. Burkitt lymphoma cell lines phenocopy the primary tumors with respect to DNA methylation and diminished PUMA expression, which can be reactivated following inhibition of DNA methyltransferases. These findings establish that PUMA is silenced in human malignancies, and they suggest PUMA as a target for the development of novel chemotherapeutics.

Published ahead of print on 23 June 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033-0850.