The leukemogenic t(8;21) fusion protein AML1-ETO controls rRNA genes and associates with nucleolar-organizing regions at mitotic chromosomes
Zaidi, Sayyed K.
Hassan, Mohammad Q.
Young, Daniel W.
Montecino, Martin A.
Lian, Jane B.
Van Wijnen, Andre J.
Stein, Janet L.
Stein, Gary S.
KeywordsCore Binding Factor Alpha 2 Subunit
Leukemia, Myeloid, Acute
RNA Polymerase I
Pol1 Transcription Initiation Complex Proteins
Nucleolus Organizer Region
Oncogene Proteins, Fusion
Amino Acids, Peptides, and Proteins
Nucleic Acids, Nucleotides, and Nucleosides
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AbstractRUNX1/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.
J Cell Sci. 2008 Dec 1;121(Pt 23):3981-90. Epub 2008 Nov 11. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/26574