Data from Novel Mechanism of Tumor Suppression by Polarity Gene <i>Discs Large 1</i> (<i>DLG1</i>) Revealed in a Murine Model of Pediatric B-ALL

Abstract

<div>Abstract<p><i>Drosophila melanogaster discs large</i> (<i>dlg)</i> is an essential tumor suppressor gene (TSG) controlling epithelial cell growth and polarity of the fly imaginal discs in pupal development. A mammalian ortholog, <i>Dlg1</i>, is involved in embryonic urogenital morphogenesis, postsynaptic densities in neurons, and immune synapses in lymphocytes. However, a potential role for <i>Dlg1</i> as a mammalian TSG is unknown. Here, we present evidence that loss of <i>Dlg1</i> confers strong predisposition to the development of malignancies in a murine model of pediatric B-cell acute lymphoblastic leukemia (B-ALL). Using mice with conditionally deleted <i>Dlg1</i> alleles, we identify a novel “pre-leukemic” stage of developmentally arrested early B-lineage cells marked by preeminent c-Myc expression. Mechanistically, we show that in B-lineage progenitors Dlg1 interacts with and stabilizes the PTEN protein, regulating its half-life and steady-state abundance. The loss of Dlg1 does not affect the level of PTEN mRNAs but results in a dramatic decrease in PTEN protein, leading to excessive phosphoinositide 3-kinase signaling and proliferation. Our data suggest a novel model of tumor suppression by a PDZ domain-containing polarity gene in hematopoietic cancers. <i>Cancer Immunol Res; 1(6); 426–37. ©2013 AACR</i>.</p></div>