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 Prepublished online as a Blood First Edition Paper on February 13, 2003; DOI 10.1182/blood-2002-09-2857.

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Blood, 15 June 2003, Vol. 101, No. 12, pp. 4966-4974

NEOPLASIA

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

From the Department of Hematopoiesis, Holland Laboratory, American Red Cross, Rockville, MD; Department of Blood and Cell Therapy Development, Holland Laboratory, American Red Cross, Rockville, MD; Graduate Program in Molecular and Cellular Oncology, Institute for Biomedical Sciences, The George Washington University, Washington, DC; Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, ON, Canada; and Banting and Best Department of Medical Research, and Department of Molecular and Medical Genetics, University of Toronto, ON, Canada.

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 dysregulated 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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