Abstract
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.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Cell Line, Tumor
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Cell Survival
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Gene Expression Regulation, Leukemic
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Gene Regulatory Networks / genetics*
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Genes, Neoplasm / genetics
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Genome, Human / genetics
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Homeostasis / genetics
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Humans
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / classification
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Protein Binding / genetics
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-myb / metabolism
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T-Cell Acute Lymphocytic Leukemia Protein 1
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T-Lymphocytes / metabolism
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T-Lymphocytes / pathology
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Neoplasm Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-myb
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T-Cell Acute Lymphocytic Leukemia Protein 1
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TAL1 protein, human