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.
| Lehrnbecher, T; Foster, C B; Zhu, S et al. (1999) Variant genotypes of the low-affinity Fcgamma receptors in two control populations and a review of low-affinity Fcgamma receptor polymorphisms in control and disease populations. Blood 94:4220-32 |
