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Title

The Role of Dlg1 in Early B cell Development and Oncogenic Transformation

Date of Award

Spring 5-15-2013

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

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.

Language

English (en)

Chair and Committee

Wojciech Swat

Committee Members

Deepta Bhattacharya, Eric Duncavage, Gene Oltz, Andrey Shaw, Barry Sleckman

Comments

Permanent URL: https://doi.org/10.7936/K7765C72

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