MOLECULAR ANALYSIS T(11--18)(Q21--Q21)--MALT LYMPHOMA

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(adapted from the investigator's abstract) MALT lymphomas constitute a recently recognized subtype of B cell non-Hodgkin's lymphomas arising in mucosa-associated lymphoid tissues (MALT), most often in the gastrointestinal tract. Among the unusual features of these tumors is an exceptionally indolent overall course, the tendency to stay localized to mucosal sites for long periods of time, the capacity to home to other mucosal sites during early stages of dissemination, proliferation in respon to or dependent upon specific bacterial antigens, and regression or elimination by antibiotic treatment of the bacterial source of the stimulat y antigen. Cytogenetic studies of these tumors indicate that almost one quarter of the cases analyzed contain a(11;18) (q21;q21) chromosomal translocation and at least another quarter have other aberrations of chromosome 18, sometimes involving the same 18q21 region. Research described in this application will analyze the molecular genetics of the t(11;18) (q21) breakpoint by first isolating genomic fragments of chromosome 18 and possible chromosome 11 DNA. These fragments will be used in turn to isolate fragments of cDNAs for genes lying at or close to the breakpoints in both chromosome 18 and 11. Full0length cDNAs for normal versions of these genes and any altered forms of these genes resulting from translocation will be isolated and their nucleotide sequence determined. Southern blot, fluorescence in situ hybridization (FISH), and RT-PCR assays for the t(11;18) (q21;q21) will be developed and used to study the distribution and specificity of this translocation in tissues of various lymphomas and hyperplastic lymphoid tissues. Finally, the functions of the genes located near the breakpoints on chromosomes 18 and 11 will be investigated by searching the cDNA sequences for homologies to known genes, determining the normal tissues in which the genes corresponding to these cDNAs are expressed, and testing the oncogenicity of the genes in the form altered as a result of the t(11;18) (q21;21) by inserting appropriate cDNA constructs into transgenic mice. Results of all of these studies will provide insights into the genetic mechanisms underlying the malignant phenotype of the neoplastic lymphocytes composing MALT lymphomas and will likely expand existing knowledge about the normal lymphocytes which represent the cellular precursors of these tumors.