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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA109901-10
Application #
8634727
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
10
Fiscal Year
2014
Total Cost
$224,001
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Frock, Richard L; Hu, Jiazhi; Meyers, Robin M et al. (2015) Genome-wide detection of DNA double-stranded breaks induced by engineered nucleases. Nat Biotechnol 33:179-86
Tepsuporn, Suprawee; Hu, Jiazhi; Gostissa, Monica et al. (2014) Mechanisms that can promote peripheral B-cell lymphoma in ATM-deficient mice. Cancer Immunol Res 2:857-66
Anderson, N M; Harrold, I; Mansour, M R et al. (2014) BCL2-specific inhibitor ABT-199 synergizes strongly with cytarabine against the early immature LOUCY cell line but not more-differentiated T-ALL cell lines. Leukemia 28:1145-8
Kwiatkowski, Nicholas; Zhang, Tinghu; Rahl, Peter B et al. (2014) Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511:616-20
Hu, Jiazhi; Tepsuporn, Suprawee; Meyers, Robin M et al. (2014) Developmental propagation of V(D)J recombination-associated DNA breaks and translocations in mature B cells via dicentric chromosomes. Proc Natl Acad Sci U S A 111:10269-74
Anders, Lars; Guenther, Matthew G; Qi, Jun et al. (2014) Genome-wide localization of small molecules. Nat Biotechnol 32:92-6
Gutierrez, Alejandro; Pan, Li; Groen, Richard W J et al. (2014) Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia. J Clin Invest 124:644-55
Mansour, Marc R; Abraham, Brian J; Anders, Lars et al. (2014) Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 346:1373-7
Knoechel, Birgit; Roderick, Justine E; Williamson, Kaylyn E et al. (2014) An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat Genet 46:364-70
Gostissa, Monica; Schwer, Bjoern; Chang, Amelia et al. (2014) IgH class switching exploits a general property of two DNA breaks to be joined in cis over long chromosomal distances. Proc Natl Acad Sci U S A 111:2644-9

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