Role of SMRT down-regulation in NHL transformation

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DESCRIPTION (provided by applicant): Molecular analysis of chromosomal abnormalities has allowed the identification of many genes directly involved in the pathogenesis of lymphoid malignancies. However, in non-Hodgkin's lymphoma (NHL), the development of the full neoplastic phenotype depends on the acquisition of multiple genetic events including concurrent activation of synergistic "dominant" oncogenes and loss of tumor suppressor gene functions. NHLs often present complex karyotypes that may prevent complete analysis. To overcome this difficulty, many transformed NHL cell lines have been established. Others and we have identified chromosome 12q24 as a recurrent breakpoint in mature lymphoid malignancies of both T- and B-cell lineage and have recently mapped the gone encoding SMRT to 12q24.3. We observed that SMRT is altered in all transformed NHL cell lines/patients tested at the genomic, transcript and protein levels. We propose that SMRT plays an important role in NHL. This implies that SMRT acts as a tumor suppressor gene. To test this hypothesis, we propose the following Specific Aims: 1-To perform a retrospective study of a large series of transformed and non-transformed patient samples by FISH, LOH and immunohistochemistry, to expand upon our observation of transformed lymphoma phenotype and deletion of one SMRT allele. 2- To study the mechanisms by which SMRT regulates apoptosis and cell survival in SMRT-deficient NHL cells. For this purpose, we will study variation of expression of a set of genes involved in cell survival and of the different caspases (and their activation) upon SMRT-restoration-driven apoptosis. The ultimate goal of this aim is to identify future investigative area for potential (new) therapeutic approaches to induce apoptosis in SMRT-deficient NHL cells. 3- To establish a cause: effect relationship between SMRT down-regulation and the NHL transformation process. For this purpose, we will use an antisense strategy to down-regulate SMRT in different normal and low-grade transgenic mice hematopoietic environment. Confirmation of the role of SMRT in NHL transformation and in apoptosis could potentially allow development of new diagnostic and prognostic tools as well as new therapeutic strategies.