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Cancer Immunol Res DOI:10.1158/2326-6066.CIR-13-0065

Novel mechanism of tumor suppression by polarity gene discs large 1 (DLG1) revealed in a murine model of pediatric B-ALL.

Publication TypeJournal Article
Year of Publication2013
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, Swat, W
JournalCancer Immunol Res
Volume1
Issue6
Pages426-37
Date Published2013 Dec
ISSN2326-6074
KeywordsAnimals, Cell Transformation, Neoplastic, Disease Models, Animal, Genes, Tumor Suppressor, Genetic Predisposition to Disease, Mice, Knockout, Neoplasm Proteins, Neoplasm Transplantation, Nerve Tissue Proteins, Phosphatidylinositol 3-Kinase, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, PTEN Phosphohydrolase, Receptors, Interleukin-7, RNA, Messenger, RNA, Neoplasm, Signal Transduction, Tumor Suppressor Protein p53
Abstract

Drosophila 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.

URLhttp://cancerimmunolres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=24778134
DOI10.1158/2326-6066.CIR-13-0065
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24778134?dopt=Abstract

Alternate JournalCancer Immunol Res
PubMed ID24778134
PubMed Central IDPMC4006353
Grant ListR37 AI057966 / AI / NIAID NIH HHS / United States
DK043351 / DK / NIDDK NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
R01AI061077 / AI / NIAID NIH HHS / United States
R01 CA125195 / CA / NCI NIH HHS / United States
CA 136470 / CA / NCI NIH HHS / United States
R01 AI073718 / AI / NIAID NIH HHS / United States
DK083756 / DK / NIDDK NIH HHS / United States
CA 125195 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R01 AI061077 / AI / NIAID NIH HHS / United States
R01DK058366 / DK / NIDDK NIH HHS / United States
R01 CA136470 / CA / NCI NIH HHS / United States
R01AI073718 / AI / NIAID NIH HHS / United States
R01 DK083756 / DK / NIDDK NIH HHS / United States
R37-AI57966 / AI / NIAID NIH HHS / United States
R01 DK058366 / DK / NIDDK NIH HHS / United States