Specific homeodomain-DNA interactions are required for HOX11-mediated transformation.
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.
Owens
Bronwyn M
BM
Department of Hematopoiesis, Holland Laboratory, American Red Cross, Rockville, MD 20855, USA.
Zhu
Yuan-Xiao
YX
Suen
Ting-Chung
TC
Wang
Pei-Xiang
PX
Greenblatt
Jack F
JF
Goss
Paul E
PE
Hawley
Robert G
RG
D016475:3T3 Cells; D000444:Aldehyde Dehydrogenase / Q000235:genetics; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004247:DNA / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000235:genetics; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D015513:Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D050697:Retinal Dehydrogenase; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D014162:Transfection
D018398:Homeodomain Proteins; D007527:Isoenzymes; D015513:Oncogene Proteins; C487378:Tlx1 protein, mouse; D004247:DNA; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase