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 TAL1/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-LBL): Results from Takaomi Sanda in Tom Look's laboratory, obtained in collaboration with Rick Young and Lee Lawton of project 5, identified 311 genes whose promoters are bound by TAL1 by ChlP-Chip analysis and that are also significantly up- or down-regulated by TAL1 knock-down. These results led to the current project proposal, which seeks to test the above central hypothesis in three specific aims: (1) delineate the transcriptional networks regulated by TAL1, and its binding-partners E2A, HEB, GATA3, LMO1 and LMO2, by identifying both the coding and non-coding genes directly bound by TAL1 and whose expression levels are regulated by TAL1 in T-ALL/LBL;(2) Delineate the transcriptional networks regulated by TAL1 in concert with its transformation collaborators NOTCHI, MYB and LEF1, and the "second-tier" transcription factors directly regulated by TAL1 in TALL/LBL;and (3) Determine by gene knock-down or over-expression which regulatory networks and specific genes are required to maintain the aberrant survival and the sustained growth of T-ALL cells transformed by TAL1. Frequent ongoing interactions with investigators in this program with expertise in genome-scale location analysis (Rick Young, Project 5), T-cell development (Harald von Boehmer, Project 2), cell cycle regulation (Piotr Sicinski, Project 3), regulation of chromosome stability (Fred Alt, Project 4), and gene expression arrays (Donna Neuberg, Biostatistics Core), will greatly enhance the likelihood of generating important discoveries from these aims.
Successful completion of this 5-year renewal will improve understanding of how regulatory pathways downstream of the TAL1/SCL oncogenic transcription factor contribute to the molecular pathogenesis of T-cell leukemias and lymphomas (T-ALL/LBL). In addition, a long-range goal is for the information gained on functionally important downstream targets of TALI to pinpoint important target genes whose inhibition will lead to the development of new and highly specific treatment strategies for these two highly related diseases.
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