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Prepublished online as a Blood First Edition Paper on February 13, 2003; DOI 10.1182/blood-2002-09-2857.
Submitted September 18, 2002
Accepted February 5, 2003
Specific homeodomain-DNA interactions are required for HOX11-mediated transformation
Bronwyn M Owens, Yuan-Xiao Zhu, Ting-Chung Suen, Pei-Xiang Wang, Jack F Greenblatt, Paul E Goss, and Robert G Hawley*
Hematopoiesis Department, American Red Cross Holland Laboratory, Rockville, MD, USA; Graduate Program in Molecular and Cellular Oncology, The George Washington University Institute for Biomedical Sciences, Washington, DC, USA
Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, ON, Canada
Banting and Best Department of Medical Research and Department of Molecular and Medical Genetics, University of Toronto, Toronto, ON, Canada
Hematopoiesis Department, American Red Cross Holland Laboratory, Rockville, MD, USA; Blood and Cell Therapy Development, American Red Cross Holland Laboratory, Rockville, MD, USA; Graduate Program in Molecular and Cellular Oncology, The George Washington University Institute for Biomedical Sciences, Washington, DC, USA
* Corresponding author; email: hawleyr{at}usa.redcross.org.
HOX11 encodes a homeodomain protein that is aberrantly expressed in T-cell acute lymphoblastic leukemia as a consequence of the t(10;14) and t(7;10) chromosomal translocations. We previously reported that HOX11 immortalizes murine hematopoietic progenitors and induces pre-T-cell tumors in mice after long latency. It has been demonstrated in a number of studies that HOX11, similar to other homeodomain proteins, binds DNA and transactivates transcription. These findings suggest that translocation-activated HOX11 functions as an oncogenic transcription factor. Here we report that HOX11 represses transcription through both TATA-containing and TATA-less promoters. Interestingly, transcriptional repression by HOX11 is independent of its DNA binding capability. Moreover, a systematic mutational analysis indicated that repressor activity was separable from immortalizing function, which requires certain residues within the HOX11 homeodomain that make base-specific or phosphate-backbone contacts with DNA. We further showed that the pathologic action of HOX11 involves DNA binding-dependent transcriptional pathways that are distinct from those controlling expression of a chromosomal target gene (Aldh-1). We conclude that dysegulated expression of a particular set of downstream target genes by DNA binding via the homeodomain is of central importance for leukemia initiation mediated by HOX11.
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