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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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NEOPLASIA
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. Shirley Liu,
Richard A. Young, and
A. Thomas Look
From the Institute for Cancer Genetics–Columbia University, New York, NY; Whitehead Institute for Biomedical Research, Cambridge, MA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA; Joint Centers for Systems Biology–Columbia University, New York, NY; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA; Departments of Pediatrics and Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM; and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA.
Aberrant expression of 1 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 basic helix-loop-helix (bHLH) transcription factor oncogene aberrantly expressed in 60% of human T-ALLs. We used chromatin immunoprecipitation (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 with -nonexpressing 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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