The long-term goal of this proposal is to gain insight into the cellular and molecular mechanisms underlying B cell clonal expansion and malignant transformation in AIDS-associated non Hodgkin's lymphoma (NHL). As a result of the introduction of relatively effective anti-retroviral therapy and the consequent higher survival rate, NHLs have become important causes of pathology in AIDS patients. In these patients, most NHLs are Burkitt- type B cell lymphomas, and display features similar to those of sporadic Burkitt's lymphoma (BL) occurring in HIV-negative patients, including t(8;14), t(8;22) or t(2;8) chromosomal translocation and c-myc proto- oncogene activation. This represents an important, but not, perhaps, sufficient event in lymphomagenesis. Full malignant transformation would require either activation of a second proto-oncogene or a stochastic second event, such as infection with Epstein-Barr virus (EBV), a powerful B lymphotropic transforming agent. EBV is present in virtually all endemic (African) BLs, but it is found only in a minority of AIDS BLs, suggesting that other B cell """"""""driving"""""""" cofactors underlie the malignant transformation of these lymphocytes. This view is further supported by the generalized B cell """"""""hyperactivity"""""""", often associated with lymph node follicular hyperplasia, found in a significant proportion of AIDS patients prior to tumoral outgrowth; and by our preliminary findings showing that the variable segments of the specific anti-rd blood cell i/I antigen autoantibodies produced by two different AIDS-associated BLs bear imprints (somatic point-mutations) that are characteristic of a persistent antigenic stimulation. We hypothesize that a mechanism of self or foreign antigen-driven B cell clonal expansion and selection precedes and/or is associated with the cellular events leading to malignant transformation in AIDS BL. Conversely, antigenic stimulation may play a less important or negligible role in the emergence and/or sustenance of neoplastic B cells in the endemic variety of BL. To test our hypothesis, we propose to analyze the antigen specificity of the antibodies produced by AIDS BLs, and determine whether their variable segments contain somatic point- mutations in a fashion consistent with a process of antigen-driven clonal selection of such mutations. In addition, we propose to verify whether progenitors of the neoplastic clonotype are present among """"""""non-neoplastic"""""""" B cells, as defined by phenotypic and genotypic analysis, obtained prior to tumoral outgrowth. The molecular features of AIDS BL will be compared with those derived from the analysis of the sporadic and endemic forms of the tumor. The demonstration that a process of Ag-driven clonal expansion and selection is an important event or cofactor, along with the characteristic genetic lesions, in AIDS-associated lymphomagenesis would provide one of the first indications that the inherent function of the (immune) cells involved in the neoplastic process are crucial for tumor development, and may provide the basis for specific immune intervention.
Showing the most recent 10 out of 12 publications
