The leukemogenic t(8;21) fusion protein AML1-ETO controls rRNA genes and associates with nucleolar-organizing regions at mitotic chromosomes
Author:
Bakshi Rachit1, Zaidi Sayyed K.1, Pande Sandhya1, Hassan Mohammad Q.1, Young Daniel W.1, Montecino Martin2, Lian Jane B.1, van Wijnen Andre J.1, Stein Janet L.1, Stein Gary S.1
Affiliation:
1. Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, MA 01655, USA 2. Departamento de Bioquimica y Biologia Molecular, Universidad de Concepcion, Facultad de Ciencias Biologicas, Concepcion, Chile
Abstract
RUNX1/AML1 is required for definitive hematopoiesis and is frequently targeted by chromosomal translocations in acute myeloid leukemia (AML). The t(8;21)-related AML1-ETO fusion protein blocks differentiation of myeloid progenitors. Here, we show by immunofluorescence microscopy that during interphase, endogenous AML1-ETO localizes to nuclear microenvironments distinct from those containing native RUNX1/AML1 protein. At mitosis, we clearly detect binding of AML1-ETO to nucleolar-organizing regions in AML-derived Kasumi-1 cells and binding of RUNX1/AML1 to the same regions in Jurkat cells. Both RUNX1/AML1 and AML1-ETO occupy ribosomal DNA repeats during interphase, as well as interact with the endogenous RNA Pol I transcription factor UBF1. Promoter cytosine methylation analysis indicates that RUNX1/AML1 binds to rDNA repeats that are more highly CpG methylated than those bound by AML1-ETO. Downregulation by RNA interference reveals that RUNX1/AML1 negatively regulates rDNA transcription, whereas AML1-ETO is a positive regulator in Kasumi-1 cells. Taken together, our findings identify a novel role for the leukemia-related AML1-ETO protein in epigenetic control of cell growth through upregulation of ribosomal gene transcription mediated by RNA Pol I, consistent with the hyper-proliferative phenotype of myeloid cells in AML patients.
Publisher
The Company of Biologists
Reference62 articles.
1. Barseguian, K., Lutterbach, B., Hiebert, S. W., Nickerson, J., Lian, J. B., Stein, J. L., van Wijnen, A. J. and Stein, G. S. (2002). Multiple subnuclear targeting signals of the leukemia-related AML1/ETO and ETO repressor proteins. Proc. Natl. Acad. Sci. USA99, 15434-15439. 2. Bernardin-Fried, F., Kummalue, T., Leijen, S., Collector, M. I., Ravid, K. and Friedman, A. D. (2004). AML1/RUNX1 increases during G1 to S cell cycle progression independent of cytokine-dependent phosphorylation and induces cyclin D3 gene expression. J. Biol. Chem.279, 15678-15687. 3. Biggs, J. R., Peterson, L. F., Zhang, Y., Kraft, A. S. and Zhang, D. E. (2006). AML1/RUNX1 phosphorylation by cyclin-dependent kinases regulates the degradation of AML1/RUNX1 by the anaphase-promoting complex. Mol. Cell. Biol.26, 7420-7429. 4. Budde, A. and Grummt, I. (1999). p53 represses ribosomal gene transcription. Oncogene18, 1119-1124. 5. Burel, S. A., Harakawa, N., Zhou, L., Pabst, T., Tenen, D. G. and Zhang, D. E. (2001). Dichotomy of AML1-ETO functions: growth arrest versus block of differentiation. Mol. Cell. Biol.21, 5577-5590.
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