TY - JOUR
T1 - Novel mechanism of tumor suppression by polarity gene discs large 1 (DLG1) revealed in a murine model of pediatric B-ALL
AU - Sandoval, Gabriel J.
AU - Graham, Daniel B.
AU - Gmyrek, Grzegorz B.
AU - Akilesh, Holly M.
AU - Fujikawa, Keiko
AU - Sammut, Benedicte
AU - Bhattacharya, Deepta
AU - Srivatsan, Shuba
AU - Kim, Alfred
AU - Shaw, Andrey S.
AU - Yang-Iott, Katherine
AU - Bassing, Craig H.
AU - Duncavage, Eric
AU - Xavier, Ramnik J.
AU - Swat, Wojciech
N1 - Publisher Copyright:
©2013 AACR.
PY - 2013/12/1
Y1 - 2013/12/1
N2 - 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.
AB - 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.
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U2 - 10.1158/2326-6066.CIR-13-0065
DO - 10.1158/2326-6066.CIR-13-0065
M3 - Article
C2 - 24778134
AN - SCOPUS:85003056246
SN - 2326-6066
VL - 1
SP - 426
EP - 437
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 6
ER -