Abstract

Research proposed in this application will investigate a number of genetic problems directly or indirectly related to human B cell neoplasia and having both clinical and basic biologic ramifications. Five projects are planned. These involve the following: (1) Analysis of the multi-clonality of lymphoproliferative lesions in immunosuppressed patients. This project will utilize restriction fragment length polymorphisms of the fused termini of Epstein-Barr virus genomes as markers of clonal cellular proliferation to determine whether or not separate lymphoproliferative lesions in individual patients arise from independent transformation events. (2) Analysis of human non- immunoglobulin gene DNA which contains strong sequence homology to DNA of the immunoglobulin heavy chain enhancer region. In addition to cloning, sequencing, and mapping this DNA on the human genome, studies will be carried out to determine possible functions of this DNA and its flanking sequences. (3) Molecular cloning and structural analysis of DNA corresponding to cytologic breakpoints involved in the t(4;11)(q21;q23) chromosomal translocation of common acute lymphocytic leukemia. DNA sequences cloned in this project will be used as hybridization probes to analyze sites of rearrangement and transcription in human B cell tumors. (4) Investigation of somatic hypermutation in rearranged immunoglobulin genes of B cell lymphomas and cell lines. The basic biology of somatic mutation will be studied by cloning and sequencing immunoglobulin genes and cDNA from tumors and cultured cells. Attempts will also be made to develop an in vitro tissue culture system for analysis of somatic mutation in both endogenous and transfected immunoglobulin genes. (5) Investigation of the possible evolution of multiple myeloma from myeloma-related clonal B cells. Immunoglobulin DNA cloned from bone marrow and blood specimens of myeloma patients will be analyzed to determine whether or not the neoplastic plasma cells in this disease develop by a multistep mechanism involving clonal B cells. In addition, this project will investigate somatic mutation in the immunoglobulin genes of plasma cells and their late B cell precursors.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA038621-09
Application #
3176712
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1985-01-01
Project End
1994-06-30
Budget Start
1992-09-01
Budget End
1994-06-30
Support Year
9
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Poteat, H T; Sklar, J (1997) A simplified polymerase chain reaction assay for detection of chromosomal translocations in hematologic malignancies. Diagn Mol Pathol 6:3-9
Kuo, F C; Sklar, J (1997) Augmented expression of a human gene for 8-oxoguanine DNA glycosylase (MutM) in B lymphocytes of the dark zone in lymph node germinal centers. J Exp Med 186:1547-56
Davi, F; Gocke, C; Smith, S et al. (1996) Lymphocytic progenitor cell origin and clonal evolution of human B-lineage acute lymphoblastic leukemia. Blood 88:609-21
Hasserjian, R P; Aster, J C; Davi, F et al. (1996) Modulated expression of notch1 during thymocyte development. Blood 88:970-6
Pear, W S; Aster, J C; Scott, M L et al. (1996) Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med 183:2283-91
Tycko, B; Ritz, J; Sallan, S et al. (1992) Changing antigen receptor gene rearrangements in a case of early pre-B cell leukemia: evidence for a tumor progenitor cell with stem cell features and implications for monitoring residual disease. Blood 79:481-8
Aster, J C; Kobayashi, Y; Shiota, M et al. (1992) Detection of the t(14;18) at similar frequencies in hyperplastic lymphoid tissues from American and Japanese patients. Am J Pathol 141:291-9
Kobayashi, Y; Tycko, B; Soreng, A L et al. (1991) Transrearrangements between antigen receptor genes in normal human lymphoid tissues and in ataxia telangiectasia. J Immunol 147:3201-9
Ellisen, L W; Bird, J; West, D C et al. (1991) TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66:649-61
Tycko, B; Smith, S D; Sklar, J (1991) Chromosomal translocations joining LCK and TCRB loci in human T cell leukemia. J Exp Med 174:867-73

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