期刊
CANCER CELL
卷 22, 期 2, 页码 209-221出版社
CELL PRESS
DOI: 10.1016/j.ccr.2012.06.007
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资金
- National Cancer Institute [5P01CA109901, 5P01CA68484, 1K99CA157951]
- National Institutes of Health, National Cancer Institute, Center for Cancer Research
- William Lawrence and Blanche Hughes Foundation
- Children's Leukemia Research Association
- Japan Society for the Promotion of Science
- California Institute for Regenerative Medicine Leukemia Team
The oncogenic transcription factor TAL1/SCL is aberrantly expressed in over 40% of cases of human T cell acute lymphoblastic leukemia (T-ALL), emphasizing its importance in the molecular pathogenesis of T-ALL. Here we identify the core transcriptional regulatory circuit controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3, and RUNX1. We show that TAL1 forms a positive interconnected autoregulatory loop with GATA3 and RUNX1 and that the TAL1 complex directly activates the MYB oncogene, forming a positive feed-forward regulatory loop that reinforces and stabilizes the TAL1-regulated oncogenic program. One of the critical downstream targets in this circuitry is the TRIB2 gene, which is oppositely regulated by TAL1 and E2A/HEB and is essential for the survival of T-ALL cells.
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