Human follicular lymphoma is one of the most common non-Hodgkin's lymphomas in the United States. Histologically the tumor cells form discrete nodules which resemble germinal centers and contain the neoplastic B cells. Molecularly the tumor is characterized by the t(14;18) chromosomal translocation which occurs in the pre-B cell as an error of immunoglobulin heavy chain V-D-J recombination. Thus, additional steps must occur subsequent to the chromosomal translocation int he pre-B cell in the genesis of this B cell malignancy. We have recently described two events which follow the t(14;18) translocation: an interstitial deletion of the immunoglobulin heavy chain allele on the der(14) chromosome; an the clonal expansion of the tumor cell clone under selection of the immunoglobulin hypervariable regions. The interstitial deletion apparently is a non-physiological class switch deletion usually involving a switch from Cmu to Cgamma1. This deletion alters the relative positions of the immunoglobulin heavy chains enhancers, Emu and Ealpha.
The first aim i s to examine the role of the Emu and Ealpha enhancers in the expression of the bcl-2 proto-oncogene. Furthermore, to directly examine the impact of the interstitial deletion on the expression of bcl-2, we will create deletion variants of a t(14;18) positive cell line which does not have the deletion. We will also undertake structural studies to define the molecular basis of the interstitial deletion of the translocated immunoglobulin locus. The exact extent of the deletion will be determined to prove it is the result of a non-physiologic class switch deletion. The structure of the DNA downstream of the breakpoint will be examined by comparing the patterns of methylation of the heavy chain switch regions of the productively rearranged and translocated immunoglobulin alleles which will provide information about the mechanism of this deletion. The goal of these studies is to define the mechanism and biological impact of this consistently observed interstitial deletion of the der(14) chromosome in follicular lymphoma.
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