In leukemias, non-random chromosomal translocations have been determined to predispose or cause changes in cell growth and/or survival that promote malignancy. The detailed study of the mechanisms of human cancer causing genes and their protein structure requires the identification or development of animal models to allow the study of protein function. Patients with the disease ataxia telangiectasia (AT) frequently suffer from T cell chromic lymphocytic leukemia (T-CLL) carrying a 14q32.1-q11 inversion/translocation. The chromosomal breakpoint gene Tcll and the related MTCP1 genes have been recently cloned and characterized and the gene responsible for their underlying disease (ATM) has been cloned and a null mutation produced in mice (Atm-/-). We hypothesize that Tcll plays a critical role in the development of cancer. Further the use of the newly isolated murine Tcll gene for the development of a mouse model of lymphoproliferation will provide an ideal opportunity to study the Tcll protein and its role in inducing mature T cell lymphoproliferations that lead to CLL. Consequently, we propose three experimental aims: 1 Evaluate the expression of Tcll during murine embyrogenesis. The spatial expression of Tcll will be critical for null mutant analysis and functional studies. 2 Develop and analyze Tcll transgenic and Tcll -/- null mutant mice. These strains will be required for the full development of an animal model of human disease. 3 Establish a mammalian model of T cell lymphoproliferation and CLL. Tcll -/- mutant mice will be bred with other mouse strains, such as the Atm +/- mice to recapitulate human CLL. We expect that through the development of these molecular tools, including a murine model of CLL, therapies for the human disease can be developed and tested.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA076259-04
Application #
6589994
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2002-05-03
Project End
2003-04-30
Budget Start
Budget End
Support Year
4
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Type
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Thompson, Lorraine H; Whiston, Roy A; Rakhimov, Yerzhan et al. (2010) A LIF/Nanog axis is revealed in T lymphocytes that lack MARCH-7, a RINGv E3 ligase that regulates the LIF-receptor. Cell Cycle 9:4213-21
Almanza, Gonzalo; Fernandez, Antonio; Volinia, Stefano et al. (2010) Selected microRNAs define cell fate determination of murine central memory CD8 T cells. PLoS One 5:e11243
Garzon, Ramiro; Liu, Shujun; Fabbri, Muller et al. (2009) MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood 113:6411-8
Ghosh, Asish K; Shanafelt, Tait D; Cimmino, Amelia et al. (2009) Aberrant regulation of pVHL levels by microRNA promotes the HIF/VEGF axis in CLL B cells. Blood 113:5568-74
Pufnock, Jeff S; Rothstein, Jay L (2009) Oncoprotein signaling mediates tumor-specific inflammation and enhances tumor progression. J Immunol 182:5498-506
Croce, Carlo M (2009) Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet 10:704-14
Volinia, Stefano; Mascellani, Nicoletta; Marchesini, Jlenia et al. (2008) Genome wide identification of recessive cancer genes by combinatorial mutation analysis. PLoS One 3:e3380
Garzon, Ramiro; Garofalo, Michela; Martelli, Maria Paola et al. (2008) Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin. Proc Natl Acad Sci U S A 105:3945-50
Garzon, Ramiro; Volinia, Stefano; Liu, Chang-Gong et al. (2008) MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood 111:3183-9
Tili, Esmerina; Michaille, Jean-Jacques; Cimino, Amelia et al. (2007) Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol 179:5082-9

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