1. ¹Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN, USA
2. ²Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
3. ³Department of Cell Biology, University of Massachusetts Medical School, Worchester, MA, USA

Correspondence: Dr CM Eischen, Department of Pathology, Vanderbilt University Medical Center, MCN C3321, 1161 21st Avenue South, Nashville, TN 37232-2561, USA. E-mail: christine.eischen@vanderbilt.edu

Received 6 April 2007; Revised 1 August 2007; Accepted 13 August 2007; Published online 10 September 2007.

Abstract

Mdm2, a regulator of the p53 tumor suppressor, is frequently overexpressed in lymphomas, including lymphomas that have inactivated p53. However, the biological consequences of Mdm2 overexpression in lymphocytes are not fully resolved. Here, we report that increased expression of Mdm2 in B cells augmented proliferation and reduced susceptibility to p53-dependent apoptosis, which was due to inhibition of p53 and suppression of p21 expression. Notably, developing and mature B cells from Mdm2 transgenic mice had an increased frequency of chromosomal/chromatid breaks and/or aneuploidy. This Mdm2-mediated genome instability occurred at a similar frequency as that in B cells overexpressing the oncogene c-Myc, but the chromosomal instability was not further enhanced when Mdm2 and c-Myc were overexpressed together. Elevated Mdm2 expression alone increased the occurrence of B-cell transformation in vivo and cooperated with c-Myc overexpression, resulting in an acceleration of B-cell lymphomagenesis. In addition, the frequency of p53 mutations was reduced, but not eliminated, in lymphomas arising in Mdm2/E-myc double transgenic mice. Therefore, increased Mdm2 expression facilitated B-cell lymphomagenesis, in part, through regulation of p53 by altering B-cell proliferation and susceptibility to apoptosis, and by inducing chromosomal instability.