| The ability to properly maintain and control cell polarity, migration and cell cycle induction are hallmarks of normal cellular development; moreover, disruption of any or all of these processes can result in tumorigenesis. Polarity genes regulate many aspects of cell polarity including: proliferation, survival, differentiation and cell migration. D. melanogaster discs large (dlg) gene is essential in drosophila development by controlling polarity and growth of epithelial cells in imaginal discs. A mammalian homolog, Dlg1, is involved in embryo morphogenesis, orchestration of post-synaptic densities in adult neurons, and lymphocyte function. However, a potential involvement of Dlg1 in lymphoid lineage malignancies remains unknown.;During early stages of B-lineage differentiation in bone marrow, signals emanating from IL-7R and pre-BCR are thought to synergistically induce proliferative expansion of progenitor cells. Paradoxically, loss of pre-BCR-signaling components is associated with leukemia in both mice and humans. Exactly how progenitor B cells perform the task of balancing proliferative burst dependent on IL-7 with the termination of IL-7 signals initiating L chain gene rearrangement remains to be elucidated.;In this study we show that loss of Dlg1 in B-lineage precursors leads to a developmental arrest at a novel pre-leukemic stage of pre-B cell differentiation characterized by expression of c-Myc and exaggerated response to IL-7. Furthermore, we provide genetic and functional evidence that the cessation of the IL-7 response of pre-B cells is controlled via a cell autonomous mechanism that operates at a discrete developmental transition inside Fraction C' (large pre-BII). Our data indicate that pre-BCR cooperates with IL-7R in expanding the pre-B cell pool, but is also critical to control the differentiation program silencing the c-Myc gene in large pre-B cells. Mechanistically, we show that Dlg1 interacts with and stabilizes PTEN protein by regulating its half-life. Accordingly, Dlg1-loss leads to dramatically diminished PTEN protein, but not mRNA, expression and excessive PI3K signaling. Strikingly, when placed in a "sensitized" tumor model, mice lacking Dlg1 succumbed to a variety of B-lineage tumors and displayed increased mortality rates compared to control cohorts. Thus, our data reveal a novel mechanism of tumor suppression by a mammalian MAGUK protein in hematopoietic lineage. |
