MOLECULAR PATHOLOGY OF HUMAN LYMPOID MALIGNANCIES

The general objective of this research project is to identify genetic lesions involved in the pathogenesis of non-Hodgkin lymphoma (NHL) and to test their diagnostic and prognostic significance. The following specific aims will be pursued: 1. Characterization and testing of the clinico-prognostic significance of structural alterations of the BCL-6 gene. We have recently identified a novel candidate protooncogene, BCL-6, which is involved in chromosomal translocations affecting 3q27 and is rearranged in up to 45% of diffuse large cell NHL, the most significant NHL type in terms of morbidity and mortality. Based on these results we will: i) Characterize the repertoire of structural alterations (rearrangements/mutations) affecting the BCL-6 gene in NHL; ii) Test the utility of BCL-6 alterations as clinico- pathologic markers by screening a large panel of NHL and correlating the results with a number of relevant clinical parameters. 2. Molecular analysis of chromosomal translocations affecting 9pl3 and l0q24 in NHL. Alterations involving chromosomal regions 9pl3 and 10q24 are detectable in 10-15% of NHL at the cytogenetic level and may be more frequent at the molecular level. We plan to clone the regions involved in the chromosomal breakpoints, search for the involved genes and define their alterations in NHL. Once these alterations will be defined, their clinico-pathologic relevance will be determined as in Specific Aim l. 3. Identification of altered apoptosis-resistance (APR) genes in NHL. Our preliminary data indicate that a significant fraction of NHL cases contain DNA sequences which are able to cause resistance to apoptosis in a novel assay involving the transfection of total tumor DNA into MYC-transfected Rat-1 cells and induction of apoptosis by serum deprivation. We plan to characterize these sequences, identify the putative APR genes, identify the nature of the activating mutations and determine their frequency in lymphoid malignancies. Eventually, we will test the utility of these alterations as clinico-pathologic markers as in Specific Aim 1. Taken together the results of these studies should lead to further understanding of the pathogenesis of NHL and provide markers for improved diagnosis, prognosis and clinical monitoring of this heterogeneous group of neoplasms.