Abstract

Many leukemias and lymphomas are strongly associated with non-random chromosomal translocations. Many of the most intensely studied translocations have been proven to be causal events in the development of leukemias. The molecular events resulting in these translocations have not been well characterized and are the focus of this application. The first specific aim seeks to characterize site-specific double strand DNA cleavage within the MLL locus induced by topo II inhibitors.
The second aim seeks to characterize site-specific DNA cleavage induced by topo II inhibitors in two additional loci AML-1 and RARA.
The third aim i s to develop a general in vitro model system of topo II inhibitor induced translocations and to identify regions of the genome prone to chromosomal translocations.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073773-02
Application #
2654273
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Wolpert, Mary K
Project Start
1997-04-01
Project End
2001-01-31
Budget Start
1998-02-01
Budget End
1999-01-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263

  Publications

Lee, Imsang; Dong, Ken C; Berger, James M (2013) The role of DNA bending in type IIA topoisomerase function. Nucleic Acids Res 41:5444-56
Stanulla, M; Chhalliyil, P; Wang, J et al. (2001) Mechanisms of MLL gene rearrangement: site-specific DNA cleavage within the breakpoint cluster region is independent of chromosomal context. Hum Mol Genet 10:2481-91
Ploski, J E; Aplan, P D (2001) Characterization of DNA fragmentation events caused by genotoxic and non-genotoxic agents. Mutat Res 473:169-80
Ahuja, H G; Felix, C A; Aplan, P D (2000) Potential role for DNA topoisomerase II poisons in the generation of t(11;20)(p15;q11) translocations. Genes Chromosomes Cancer 29:96-105
Thandla, S; Alashari, M; Green, D M et al. (1999) Therapy-related T cell lymphoblastic lymphoma with t(11;19)(q23;p13) and MLL gene rearrangement. Leukemia 13:2116-8
Chervinsky, D S; Zhao, X F; Lam, D H et al. (1999) Disordered T-cell development and T-cell malignancies in SCL LMO1 double-transgenic mice: parallels with E2A-deficient mice. Mol Cell Biol 19:5025-35
Ahuja, H G; Felix, C A; Aplan, P D (1999) The t(11;20)(p15;q11) chromosomal translocation associated with therapy-related myelodysplastic syndrome results in an NUP98-TOP1 fusion. Blood 94:3258-61
Thandla, S P; Ploski, J E; Raza-Egilmez, S Z et al. (1999) ETV6-AML1 translocation breakpoints cluster near a purine/pyrimidine repeat region in the ETV6 gene. Blood 93:293-9
Sood, R; Stewart, C C; Aplan, P D et al. (1998) Neutropenia associated with T-cell large granular lymphocyte leukemia: long-term response to cyclosporine therapy despite persistence of abnormal cells. Blood 91:3372-8
Felix, C A; Megonigal, M D; Chervinsky, D S et al. (1998) Association of germline p53 mutation with MLL segmental jumping translocation in treatment-related leukemia. Blood 91:4451-6

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