Lymphomas and leukemias are frequent cancers in humans. Normal lymphocyte development involves V(D)J recombination, which generates DNA double stand breaks (DSBs) at antigen-specific receptor loci, followed by a burst of proliferation once a functional rearrangement is formed. Deregulation of V(D)J recombination could result in persistent DSBs in developing lymphocytes, which, if stimulated to proliferate, may result in genome instability and tumorigenesis. In the course of our studies on the regulation of V(D)J recombination, we generated mutant mice that lack either the transcriptional enhancer or the promoter of a variable gene segment in the T cell receptor (TCR) beta locus. Either mutation results in deregulated cleavages of gene segments during TCR beta rearrangement and, therefore, persistent DSBs in developing thymocytes. Expression of a rearranged TCR transgene, which promotes thymocyte proliferation, results in the development of T cell acute lymphoblastic lymphoma (T-ALL) in either of the mutant mouse strains. Thus, in the absence of predisposing mutations in proto-oncogenes or tumor suppressor genes, TCR expression interacts with mutations in cis-regulatory elements at the TCR beta locus to promote the development of T-ALL. This application aims to examine i) the fate of DSBs at the TCR beta locus and how their resolution contributes to tumorigenesis; ii) the role of inhibition of p53 activation in thymocytes containing DSBs in tumorigenesis, and iii) the identity of the immediate precursor T cells that give rise to T-ALL in TCR transgenic mice lacking either the enhancer or the promoter. Findings from the proposed studies may shed light on the etiology and mechanisms underlying the frequent translocations of the antigen receptor loci in lymphoid tumors in humans. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100875-04
Application #
7218670
Study Section
Special Emphasis Panel (ZRG1-SSS-1 (03))
Program Officer
Howcroft, Thomas K
Project Start
2004-04-01
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
4
Fiscal Year
2007
Total Cost
$238,942
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Internal Medicine/Medicine
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
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