The often aggressive and unpredictable behavior of T-cell malignancies continues to pose major clinical management problems in children and adults. This proposal is based on the central hypothesis that downstream target genes within TALl/SCL-mediated transcriptional networks contribute to the disordered regulation of cell proliferation, differentiation, and apoptosis in the majority of human T-cell leukemias and lymphomas (T-ALL/T-LL). Thus, the analysis of TALl-regulated genes in such malignancies is expected to reveal key transcriptional regulatory networks with essential functions in the survival and proliferation of malignant T lymphoblasts, as well as candidate genes that might be lucrative targets for therapeutic intervention. Recent data from the applicant's laboratory, obtained in collaboration with Dr. Richard Young's group at MIT and other program investigators, has provided a genome-wide spectrum of 81 different target gene promoters bound by TALl in human T-ALL cell lines. The discovery of these direct targets of TALI/SCL has lent impetus to the current project proposal, which seeks to test the above central hypothesis in three specific aims: (1) define the mechanisms through which TALl regulates the expression of its direct target genes in T-cell malignancy; (2) delineate the transcriptional regulatory networks mediated by TALl by identifying the direct targets of transcription factor genes whose expression is directly altered by TALl in malignant T-cells; and (3) elucidate the TALl-controlled genes whose expression levels contribute to the cell growth advantage and aberrant survival characteristic of malignant thymocytes transformed by this oncogene. Frequent interaction with investigators in this program with expertise in genome-scale location analysis (Dr. Young, Project 1), T-cell development (Dr. von Boehmer, Project 2), cell cycle regulation (Dr. Sicinski, Project 3), epigenetic regulation of chromosome stability (Drs. AIt and Bassing, Project 4), gene expression arrays (Drs. Neuberg and Liu, Biostatistics Core, and Dr. Fox, Molecular Core)), and computational approaches to the identification of shared binding motifs (Dr. Liu, Biostatistics Core) should greatly enhance the likelihood of generating important discoveries from these aims. Successful completion of this 5-year project will improve understanding of how regulatory pathways downstream of the TALI/SCL oncogenic transcription factor contribute to the molecular pathogenesis of T-cell leukemias and lymphomas. In addition, a long-range goal is for the information gained on functionally important downstream targets of TALl to pinpoint genes whose inhibition could lead to the development of new and highly specific treatment strategies for these two diseases.
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