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First published online 11 November 2008
doi: 10.1242/jcs.033431

Journal of Cell Science 121, 3981-3990 (2008)
Published by The Company of Biologists 2008
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Research Article

The leukemogenic t(8;21) fusion protein AML1-ETO controls rRNA genes and associates with nucleolar-organizing regions at mitotic chromosomes

Rachit Bakshi1, Sayyed K. Zaidi1, Sandhya Pande1, Mohammad Q. Hassan1, Daniel W. Young1,*, Martin Montecino2, Jane B. Lian1, Andre J. van Wijnen1, Janet L. Stein1 and Gary S. Stein1,{ddagger}

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

{ddagger} Author for correspondence (e-mail: gary.stein{at}umassmed.edu)

Accepted 8 September 2008

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.

Key words: Acute myelogenous leukemia, RUNX1, Ribosomal DNA transcription, RNA polymerase I, UBF1, Nucleolar organizing region






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