) Important advances have been made in understanding the molecular origins of human T-cell acute lymphoblastic leukemia (T-ALL). Seven T-cell-specific oncogenes - TAL1/SCL, TAL2, LYL1, LMO1, LMO2, HOX11, and TAN1 -- have been cloned to date, each being aberrantly mobilized by chromosomal translocation into the vicinity of powerful enhancers associated with the T-cell receptor loci. Although affording insight into T-ALL pathogenesis, these chromosomal translocations are found in only about 25 percent of cases overall, leaving the remainder without satisfactory explanations for treatment resistance and without clues to molecular targets for the development of new antileukemic agents. The general theme of this proposal is that T-ALL molecular pathogenesis must be reevaluated to stimulate therapeutic progress. Our central hypothesis is that a substantial fraction of T-ALL cases harbor mutations (other than those induced by chromosomal translocation) that affect key transcriptional control networks in thymocyte development, often through alterations in upstream pathways that normally silence the expression of T-ALL oncogenes in developing thymocytes.
Specific Aim 1 seeks to identify interactions and coexpression patterns among these seven genes (and their close relatives), using contemporary methods to analyze RNAs of T-lymphoblasts collected from several large series of children and adults with T-ALL, treated either within the DFCI program or at leukemia centers nationwide. In the proposed studies, oncogene expression in pretreatment cell samples will be analyzed by real-time quantitative RT-PCR and oligonucleotide microarrays to learn how T-cell oncogenes collaborate in multistep pathways leading to T-ALL in both children and adults. In concert with this effort, studies in Specific Aim 2 will capitalize on the zebrafish model system, to induce T-cell neoplasia and to conduct """"""""forward"""""""" genetic screens in vertebrates for genetic modulators of the T-cell malignant phenotype. The zebrafish system is uniquely suited for these experiments, as it affords readily accessible, transparent embryos and the opportunity to perform phenotype-driven mutational screens in an organism whose thymic development is comparable to that of humans and mice. Proposed topics of investigation include the identification of upstream mutations responsible for the misexpression of oncogenes by developing thymocytes, genetic screens for mutations that accelerate T-lineage malignancy in the presence of known activated oncogenes, and, ultimately, suppressor screens for genes whose loss of function will block the leukemic phenotype.
Specific Aims 1 and 2 will proceed in tandem, so that promising findings in either series of investigations can be rapidly incorporated into the other. The information gained from this project is likely to improve the predication of treatment responses in children and adults with T-ALL, hence improving clinical management strategies overall. Ultimately the identification of pivotal genes in the pathways that drive T-ALL could provide novel targets for T-cell-specific leukemia therapies.
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