Novel mechanism of tumor suppression by polarity gene discs large 1 (DLG1) revealed in a murine model of pediatric B-ALL.
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.
Authors' Affiliations: Broad Institute, Cambridge, Massachusetts.
Gabriel J
GJ
Sandoval
Daniel B
DB
Graham
Grzegorz B
GB
Gmyrek
Holly M
HM
Akilesh
Keiko
K
Fujikawa
Benedicte
B
Sammut
Deepta
D
Bhattacharya
Shuba
S
Srivatsan
Alfred
A
Kim
Andrey S
AS
Shaw
Katherine
K
Yang-Iott
Craig H
CH
Bassing
Eric
E
Duncavage
Ramnik J
RJ
Xavier
Wojciech
W
Swat
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D000074288:Discs Large Homolog 1 Protein; D004195:Disease Models, Animal; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020395:Receptors, Interleukin-7 / Q000502:physiology; D000074407:SAP90-PSD95 Associated Proteins; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency
D000074288:Discs Large Homolog 1 Protein; C000614189:Dlg1 protein, mouse; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D020395:Receptors, Interleukin-7; D000074407:SAP90-PSD95 Associated Proteins; D016159:Tumor Suppressor Protein p53; D058539:Phosphatidylinositol 3-Kinase; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse