Abstract
Specific Hox genes are implicated in leukemic transformation, and their selective genetic collaboration with TALE homeobox genes, Pbx and Meis, accentuates their oncogenic potential. The molecular mechanisms underlying these coordinate functions, however, have not been characterized. In this study, we demonstrate that HoxA9 requires its Pbx interaction motif as well as its amino terminus to enhance the clonogenic potential of myeloid progenitors in vitro. We further show that HoxA9 forms functional trimeric DNA binding complexes with Pbx and Meis-like proteins on a modified enhancer. DNA binding complexes containing HoxA9 and TALE homeoproteins display cooperative transcriptional activity and are present in leukemic cells. Trimeric complex formation on its own, however, is not sufficient for HoxA9-mediated immortalization. Rather, structure-function analyses demonstrate that domains of HoxA9 which are necessary for cellular transformation are coincident with those required for trimer-mediated transcriptional activation. Furthermore, the amino terminus of HoxA9 provides essential transcriptional effector properties and its requirement for myeloid transformation can be functionally replaced by the VP16 activation domain. These data suggest that biochemical interactions between HoxA9 and TALE homeoproteins mediate cellular transformation in hematopoietic cells, and that their transcriptional activity in higher order DNA binding complexes provides a molecular basis for their collaborative roles in leukemogenesis.
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Acknowledgements
These studies were supported by grants from the NIH (CA42971, AI-07290 and CA09151). CA Schnabel is a postdoctoral fellow of the Leukemia Society of America. We thank Bich-Tien Rouse for expert assistance in preparation of the HoxA9 monoclonal antibody. Neal Copeland for the Meis1a and HoxA9 cDNAs and the M1 and B112 cell lines, and J van Deursen for the VP16-HoxA9 cDNA. We also thank Phil Achacoso and Gary Nolan for the ΦNX packaging cell line.
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Schnabel, C., Jacobs, Y. & Cleary, M. HoxA9-mediated immortalization of myeloid progenitors requires functional interactions with TALE cofactors Pbx and Meis. Oncogene 19, 608–616 (2000). https://doi.org/10.1038/sj.onc.1203371
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DOI: https://doi.org/10.1038/sj.onc.1203371
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