D-type cyclins (cyclin D1, D2 and D3) are components of the core cell cycle machinery. Rearrangements of cyclin D genes and overexpression of cyclin D proteins are seen in a large number of lymphoid malignancies. Cyclins D1 and D3 were implicated to play role in formation of T-cell acute lymphoblastic leukemias (T-ALL). The best-documented function of D-type cyclins is their ability to activate cyclin-dependent kinases CDK4 and CDK6 and to allow cell cycle progression. However, there is growing evidence from several sources, including our own work, that D-cyclins play important cell cycle-independent roles. We hypothesize that aberrantly expressed cyclins D1 and D3 contribute to T-ALL formation via their association with novel partners, and facilitate T-cell transformation through mechanisms and pathways independent of the roles of these proteins in cell cycle progression. We also hypothesize that cyclin D1 contributes to T-ALL formation via different molecular mechanism than cyclin D3, i.e. through interaction with different cellular partners. In the work described this application we will study the exact molecular functions of cyclin D1 and D3 in mouse and in human T-ALL. For mouse studies, we will take advantage of a novel knock-in strain of mice expressing tandemly (FLAG- and HA-) tagged cyclin D1 in place of the wild-type protein, which was recently generated in our laboratory. We already demonstrated that this strain allows us to determine the identity of cyclin D1 protein partners (through immunoaffinity purification - mass spectrometry) and cyclin D1 genomic targets (through ChlP-chip) in essentially any major mouse organ or in tumorigenesis. We will also generate a novel mouse strain expressing tagged cyclin D3. We will use these strains to determine the identity of cyclin D1- and D3-molecular partners and targets in a Notch-driven murine model of T-ALL. We will utilize cell lines and gene-delivery systems available in von Boehmer lab to test contribution of these proteins to tumorigenesis in a mouse T-ALL model. Together with the Look lab, we will extend these analyses to human T-ALL, and we will dissect the molecular functions of cyclins D1 and D3 in the oncogenic transformation of human T-cell lineage.
The Specific Aims are as follows:
Specific Aim 1; To determine the molecular partners and targets of cyclins D1 and D3 and their contribution to tumorigenesis in a Notch-driven murine model of T-ALL.
Specific Aim 2 : To determine the molecular function of cyclins D1 and D3 in human T-ALL.
Abnormally high levels of D-type cyclins represent a driving force in several human cancers, including a large number of leukemias. It is currently unclear how D-cyclins drive malignant transformation. In this study we will dissect the molecular mechanism of cyclin D action in neoplasia using novel mouse strains and human leukemia cells. Elucidation of the molecular functions of D-cyclins is essential in order to design rational therapeutic strategies.
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