Our long-term goal is to understand the molecular mechanisms operative in proliferation and differentiation in human lymphocytes. T-cell leukemias provide an excellent resource for identification and characterization of genes that may alter proliferation/differentiation of lymphocytes. For example, molecular analysis of specific translocations in leukemic cells have led to identification of more than 15 proto-oncogenes. Furthermore, leukemic cells provide novel opportunities to identify mechanisms that may cause altered expression of proto-oncogenes, thus contributing to leukemogenesis. We have recently identified a putative proto-oncogene (Rhom-2) on chromosome Il at pl3. The Rhom-2 locus is the most frequent target of translocation involving T-cell receptor genes in T-cell acute lymphoblastic leukemias (ALL) in children suggesting that the Rhom-2 gene plays an important role in leukemogenesis. We will generate transgenic mice containing the Rhom-2 gene under an inducible promoter to directly demonstrate its role in T-cell leukemia and other tumors. Rhom-2 is not expressed in normal thymocytes or mature lymphocytes but it is highly expressed in leukemic blasts from most cases of T-ALL with llpl3 translocations. It is believed that this aberrant Rhom-2 expression contributes to leukemogenesis. We, therefore, plan to identify and characterize nucleotide sequences that control normal and inappropriate transcription of the Rhom-2 gene. In particular, we will test the hypothesis that the llpl3 translocation in most cases removes a negative transcriptional regulatory element of the Rhom-2 gene, resulting in its inappropriate expression. If our hypothesis is experimentally verified, we would have discovered a novel mechanism of proto-oncogene activation. After achieving remission, approximately one-third of the patients with T- ALL relapse due to resurgence of residual leukemic cells that cannot be detected during remission by morphologic methods. We have used a very sensitive polymerase chain reaction (PCR) based assay to detect minimum residual disease in T-ALL patients. Using a limited number of patients, we found that the PCR based assay has great potential in predicting impending relapse and in determining the efficacy of anti-leukemic therapy. We now plan to conduct a prospective study employing an adequate number of patients to assess the use of this technique in predicting relapse, monitoring the efficacy of anti-leukemic therapy, and long-term survival.
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