Our long-term goal is to understand the molecular mechanisms operative in proliferation and differentiation of lymphocytes because perturbations in these processes results in leukemias. LMO-2 (Rhom-2/RBTN-2/ttg-2) locus at chromosome 11p13 is specifically disrupted in 10% patients with childhood T cell acute lymphoblastic leukemia (ALL). The oncogenic effects of LMO-2 are T cell specific; transgenic mice over-expressing LMO-2 in all tissues do not show any type of cancer other than T cell leukemias. It is hypothesized that LMO-2 mediates leukemogenesis by binding to other transcription factors and modulates their activity. Oncogenic specificity of LMO-2 may be because it binds a transcription factor with thymocyte specific expression. Accordingly, we have identified a novel transcription factor (Elf-2) that binds LMO-2 and its pattern of expression in normal and leukemic thymocytes strongly suggests that it plays an important role in leukemogenesis. We will conduct structure-function studies of Elf-2 to define its normal function and its role in leukemogenesis. Elf-2, in association with LMO-2, may alter the expression of genes that regulate thymocyte proliferation. Thus, a complementary approach to understand the mechanism of LMO-2 action is to identify its downstream target genes whose expression is altered in leukemic cells. Recently, using Representational Difference Analysis technique, we have isolated several clones that represent potential LMO-2 target genes. Cognate mRNA for one of the cones (a23) is not expressed in normal thymocytes but it is highly expressed in expanded double negative (DN) thymocytes and every mouse T cell (but not in B lineage) leukemias. Clone a23's invariant but ectopic expression in DN thymocytes and in every T cell leukemia strongly suggests that it play an important early role in leukemogenesis. We plan to characterize full-length cDNA representing clone a23 and conduct functional studies to determine its normal function and its role in leukemogenesis. After achieving remission, approximately 30% of the patients with T cell acute lymphocytic leukemia (ALL) relapse due to the resurgence of residual leukemic cells that can not be detected during remission of morphological methods. We have used a very sensitive PCR based assay to detect the residual leukemic cells and found that it has great potential in predicting impending relapse. We are now conducting a prospective study employing 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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