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Blood, 1 August 2006, Vol. 108, No. 3, pp. 986-992.
Prepublished online as a Blood First Edition Paper on April 18, 2006; DOI 10.1182/blood-2005-08-3482.
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Submitted August 29, 2005
Accepted February 26, 2006
Transcriptional regulatory networks downstream of TAL1/SCL in t-cell acute lymphoblastic leukemia
Teresa Palomero, Duncan T Odom, Jennifer O'Neil, Adolfo A Ferrando*, Adam Margolin, Donna S Neuberg, Stuart S Winter, Richard S Larson, Wei Li, X S Liu, Richard A Young, and A T Look
Institute for Cancer Genetics, Columbia University, New York, NY, USA
Whitehead Institute for Biomedical Research, Cambridge, MA, USA
Department of Pediatric Oncolgy Department, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Joint Centers for Systems Biology, Columbia University, New York, NY, USA
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA, USA
Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
Pathology, University of New Mexico, Albuquerque, NM, USA
Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
* Corresponding author; email: af2156{at}columbia.edu.
Aberrant expression of one or more transcription factor oncogenes is a critical component of the molecular pathogenesis of human T-cell acute lymphoblastic leukemia (T-ALL), however, oncogenic transcriptional programs downstream of T-ALL oncogenes are mostly unknown. TAL1/SCL is a bHLH transcription factor oncogene aberrantly expressed in 60% of human T-ALLs. We used ChIP on chip to identify 71 direct transcriptional targets of TAL1/SCL. Promoters occupied by TAL1 were also frequently bound by the class I bHLH proteins E2A and HEB, suggesting that TAL1/E2A as well as TAL1/HEB heterodimers play a role in transformation of T-cell precursors. Using RNA interference, we demonstrated that TAL1 is required for the maintenance of the leukemic phenotype in Jurkat cells and showed that TAL1 binding can be associated with either repression or activation of genes whose promoters occupied by TAL1, E2A and HEB. In addition, oligonucleotide microarray analysis of RNA from 47 primary T-ALL samples showed specific expression signatures involving TAL1 targets in TAL1 expressing compared to non-expressing human T-ALLs. Our results indicate that TAL1 may act as a bifunctional transcriptional regulator (activator and repressor) at the top of a complex regulatory network that disrupts normal T-cell homeostasis and contributes to leukemogenesis.
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