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

Rachit Bakshi, Sayyed K. Zaidi, Sandhya Pande, Mohammad Q. Hassan, Daniel W. Young, Martin Montecino, Jane B. Lian, Andre J van Wijnen, Janet L. Stein, Gary S. Stein

Research output: Contribution to journalArticle

41 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3981-3990
Number of pages10
JournalJournal of Cell Science
Volume121
Issue number23
DOIs
StatePublished - Dec 1 2008
Externally publishedYes

Fingerprint

Ribosomal DNA
rRNA Genes
Acute Myeloid Leukemia
Chromosomes
Interphase
Genetic Translocation
Proteins
Jurkat Cells
Cytosine
Hematopoiesis
Myeloid Cells
RNA Interference
Fluorescence Microscopy
Mitosis
Epigenomics
Methylation
Leukemia
Up-Regulation
Down-Regulation
Phenotype

Keywords

  • Acute myelogenous leukemia
  • Nucleolar organizing region
  • Ribosomal DNA transcription
  • RNA polymerase I
  • RUNX1
  • UBF1

ASJC Scopus subject areas

  • Cell Biology

Cite this

The leukemogenic t(8;21) fusion protein AML1-ETO controls rRNA genes and associates with nucleolar-organizing regions at mitotic chromosomes. / Bakshi, Rachit; Zaidi, Sayyed K.; Pande, Sandhya; Hassan, Mohammad Q.; Young, Daniel W.; Montecino, Martin; Lian, Jane B.; van Wijnen, Andre J; Stein, Janet L.; Stein, Gary S.

In: Journal of Cell Science, Vol. 121, No. 23, 01.12.2008, p. 3981-3990.

Research output: Contribution to journalArticle

Bakshi, R, Zaidi, SK, Pande, S, Hassan, MQ, Young, DW, Montecino, M, Lian, JB, van Wijnen, AJ, Stein, JL & Stein, GS 2008, 'The leukemogenic t(8;21) fusion protein AML1-ETO controls rRNA genes and associates with nucleolar-organizing regions at mitotic chromosomes', Journal of Cell Science, vol. 121, no. 23, pp. 3981-3990. https://doi.org/10.1242/jcs.033431
Bakshi, Rachit ; Zaidi, Sayyed K. ; Pande, Sandhya ; Hassan, Mohammad Q. ; Young, Daniel W. ; Montecino, Martin ; Lian, Jane B. ; van Wijnen, Andre J ; Stein, Janet L. ; Stein, Gary S. / The leukemogenic t(8;21) fusion protein AML1-ETO controls rRNA genes and associates with nucleolar-organizing regions at mitotic chromosomes. In: Journal of Cell Science. 2008 ; Vol. 121, No. 23. pp. 3981-3990.
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