UMMS Affiliation

Department of Cell Biology; Graduate School of Biomedical Sciences

Publication Date

2008-11-13

Document Type

Article

Subjects

Core Binding Factor Alpha 2 Subunit; Leukemia, Myeloid, Acute; DNA, Ribosomal; Transcription, Genetic; RNA Polymerase I; Pol1 Transcription Initiation Complex Proteins; Nucleolus Organizer Region; Oncogene Proteins, Fusion

Disciplines

Amino Acids, Peptides, and Proteins | Cell Biology | Genetic Phenomena | Investigative Techniques | Neoplasms | Nucleic Acids, Nucleotides, and Nucleosides

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.

DOI of Published Version

10.1242/jcs.033431

Source

J Cell Sci. 2008 Dec 1;121(Pt 23):3981-90. Epub 2008 Nov 11. Link to article on publisher's site

Journal/Book/Conference Title

Journal of cell science

Related Resources

Link to Article in PubMed

PubMed ID

19001502

Share

COinS