B cell malignancies such as Burkitt's lymphoma (BL), AIDS-associated non-Hodgkins lymphoma (AIDS-NHL), Diffuse Large Cell B lymphomas (DLCL) and the mouse plasmacytoma (PC) present with a characteristic non-random chromosomal translocation that often results in the constitutive expression of c-MYC, an important regulator of cellular proliferation. In an attempt to regain control of c-MYC expression in these B cell malignancies, we have been studying allelic polymorphisms that express differing levels of c-MYC. The rationale behind this approach resides on a recent discovery in our laboratory that certain human c-MYC alleles are defective in expression leading to essentially monoallelic expression of a single wildtype allele. The allelic variants including CAA-33, S11N and K288S, were originally identified through a large screening of normal healthy volunteers at the NIH Blood Bank by a PCR-based SSCP assay. While the S11N and K288S alleles are endogenous to the Caucasian population, the CAA-33 allele is found almost exclusively in African or African-Americans. Both the K288S and CAA-33 alleles are found to be transcriptionally compromised in peripheral blood. Detailed studies at the gene level reveal further that the CAA-33 allele is associated with a second polymorphic change in the 5' untranslated region (5'UT) of c-MYC. Since it appears that loss of transcriptional activity is linked to this 5' UT polymorphism, our studies are now directed towards determining what transcriptional regulating molecules may bind to this region.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010024-05
Application #
6433187
Study Section
(LG)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Silva, Santiago; Wiener, Francis; Klein, George et al. (2005) Location of Myc, Igh, and Igk on Robertsonian fusion chromosomes is inconsequential for Myc translocations and plasmacytoma development in mice, but Rb(6.15)-carrying tumors prefer Igk-Myc inversions over translocations. Genes Chromosomes Cancer 42:416-26
Park, Sung Sup; Kim, Joong Su; Tessarollo, Lino et al. (2005) Insertion of c-Myc into Igh induces B-cell and plasma-cell neoplasms in mice. Cancer Res 65:1306-15
McNeil, Nicole; Kim, Joong Su; Ried, Thomas et al. (2005) Extraosseous IL-6 transgenic mouse plasmacytoma sometimes lacks Myc-activating chromosomal translocation. Genes Chromosomes Cancer 43:137-46
Cheung, Wan Cheung; Kim, Joong Su; Linden, Michael et al. (2004) Novel targeted deregulation of c-Myc cooperates with Bcl-X(L) to cause plasma cell neoplasms in mice. J Clin Invest 113:1763-73
Felix, Klaus; Gerstmeier, Simone; Kyriakopoulos, Antonios et al. (2004) Selenium deficiency abrogates inflammation-dependent plasma cell tumors in mice. Cancer Res 64:2910-7
Kovalchuk, Alexander L; Kim, Joong Su; Janz, Siegfried (2003) E mu/S mu transposition into Myc is sometimes a precursor for T(12;15) translocation in mouse B cells. Oncogene 22:2842-50
Silva, Santiago; Kovalchuk, Alexander L; Kim, Joong Su et al. (2003) BCL2 accelerates inflammation-induced BALB/c plasmacytomas and promotes novel tumors with coexisting T(12;15) and T(6;15) translocations. Cancer Res 63:8656-63