Scientific Publications

Novel Mechanism of Tumor Suppression by Polarity Gene Discs Large 1 (DLG1) Revealed in a Murine Model of Pediatric B-ALL.

Publication TypeJournal Article
AuthorsSandoval, GJ, Graham DB, Gmyrek GB, Akilesh HM, Fujikawa K., Sammut B., Bhattacharya D., Srivatsan S., Kim A., Shaw AS, Yang-Iott K., Bassing CH, Duncavage E., Xavier RJ, and Swat W.
AbstractDrosophila melanogaster discs large (dlg) is an essential tumor suppressor gene (TSG) controlling epithelial cell growth and polarity of the fly imaginal discs in pupal development. A mammalian ortholog, Dlg1, is involved in embryonic urogenital morphogenesis, postsynaptic densities in neurons, and immune synapses in lymphocytes. However, a potential role for Dlg1 as a mammalian TSG is unknown. Here, we present evidence that loss of Dlg1 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 Dlg1 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. Cancer Immunol Res; 1(6); 426-37. ©2013 AACR.
Year of Publication2013
JournalCancer immunology research
Volume1
Issue6
Pages426-37
Date Published (YYYY/MM/DD)2013/12/01
ISSN Number2326-6066
DOI10.1158/2326-6066.CIR-13-0065
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/24778134?dopt=Abstract