Data from Mice Heterozygous for Germ-line Mutations in Methylthioadenosine Phosphorylase (<i>MTAP</i>) Die Prematurely of T-Cell Lymphoma

Abstract

<div>Abstract<p>Large homozygous deletions of 9p21 that inactivate <i>CDKN2A, ARF</i>, and <i>MTAP</i> are common in a wide variety of human cancers. The role for <i>CDKN2A</i> and <i>ARF</i> in tumorigenesis is well established, but whether <i>MTAP</i> loss directly affects tumorigenesis is unclear. <i>MTAP</i> encodes the enzyme methylthioadenosine phosphorylase, a key enzyme in the methionine salvage pathway. To determine if loss of <i>MTAP</i> plays a functional role in tumorigenesis, we have created an <i>MTAP</i>-knockout mouse. Mice homozygous for a <i>MTAP</i> null allele (<i>Mtap<sup>lacZ</sup></i>) have an embryonic lethal phenotype dying around day 8 postconception. <i>Mtap/Mtap<sup>lacZ</sup></i> heterozygotes are born at Mendelian frequencies and appear indistinguishable from wild-type mice during the first year of life, but they tend to die prematurely with a median survival of 585 days. Autopsies on these animals reveal that they have greatly enlarged spleens, altered thymic histology, and lymphocytic infiltration of their livers, consistent with lymphoma. Immunohistochemical staining and fluorescence-activated cell sorting analysis indicate that these lymphomas are primarily T-cell in origin. Lymphoma-infiltrated tissues tend to have reduced levels of <i>Mtap</i> mRNA and MTAP protein in addition to unaltered levels of methyldeoxycytidine. These studies show that <i>Mtap</i> is a tumor suppressor gene independent of <i>CDKN2A</i> and <i>ARF</i>. [Cancer Res 2009;69(14):OF5961–8]</p></div>