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Molecular Biology and Genetics |
Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine [B. A. H., S. Y. D. L., E. L. K., J. Z., M. A. L.] and Pathology [B. A. H., E. L. K.], and The Penn Diabetes Center [M. A. L.], University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
AML1-ETO is an oncoprotein that can promote self-renewal of primaryhematopoietic cells by opposing the activity of AML1. Two domains, Nervy-homology(NH) 2 and NH4, have been implicated in the recruitment of corepressors by AML1-ETO, but the relative roles of NH2 and NH4 vary in different cell lines and have not been examined in nonimmortalized cells. Here, we have used a series of differentiation, proliferation, and self-renewal assays in an effort to determine the roles of the NH domains using progenitor-enriched primary bone marrow cells. In these assays, deletion of NH2 or NH4, individually, has a minimal effect on AML1-ETO function, and the mutants retain the ability to promote long-term expansion of cells. In contrast, the double deletion of NH2 and NH4 eliminates the activity of the fusion protein. Thus, the double deletion of NH2 and NH4 produces a functional deficit greater than the sum of the individual deletions. These findings suggest that the NH2 and NH4 domains function cooperatively in the corepressor environment of primary bone marrow cells.
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