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

Abstract

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.

SUPPLEMENTAL MATERIAL

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

ACKNOWLEDGMENTS

We thank the Hartwell Center and Flow Cytometry and Cell Sorting Facility at St. Jude Children's Research Hospital for their technical assistance, John T. Sandlund for providing the BL samples, Guangchun Son for bioinformatic analyses, and Jeremy Graff for critically reading the manuscript.

This work was supported in part by NIH grants (CA63230, CA71907, CA76379, and CA73544) and NIH/NCI Cancer Center Support CORE grant CA21765. We are also grateful to the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital for their generous support.