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

Gabriel J. Sandoval, Daniel B. Graham, Grzegorz B. Gmyrek, Holly M. Akilesh, Keiko Fujikawa, Benedicte Sammut, Deepta Bhattacharya, Shuba Srivatsan, Alfred Kim, Andrey S. Shaw, Katherine Yang-Iott, Craig H. Bassing, Eric Duncavage, Ramnik J. Xavier, Wojciech Swat

Research output: Contribution to journalArticle

21 Scopus citations

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.

Original languageEnglish
Pages (from-to)426-437
Number of pages12
JournalCancer immunology research
Volume1
Issue number6
DOIs
StatePublished - Dec 1 2013
Externally publishedYes

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    Sandoval, G. J., Graham, D. B., Gmyrek, G. B., Akilesh, H. M., Fujikawa, K., Sammut, B., Bhattacharya, D., Srivatsan, S., Kim, A., Shaw, A. S., Yang-Iott, K., Bassing, C. H., Duncavage, E., Xavier, R. J., & Swat, W. (2013). Novel mechanism of tumor suppression by polarity gene discs large 1 (DLG1) revealed in a murine model of pediatric B-ALL. Cancer immunology research, 1(6), 426-437. https://doi.org/10.1158/2326-6066.CIR-13-0065