"The t(8;21) fusion protein, AML1–ETO, specifically represses the transcription of the p14ARF tumor suppressor in acute myeloid leukemia".

Bryan Linggi ^1,, Carsten Müller-Tidow ^{2, *}, Louis van de Locht ^{3, *}, Ming Hu ^{4, *}, John Nip ¹, Hubert Serve ², Wolfgang E. Berdel ², Bert van der Reijden ³, Dawn E. Quelle ⁵, Janet D. Rowley ⁶, John Cleveland ⁷, Joop H. Jansen ³, Pier Paolo Pandolfi ⁴ & Scott W. Hiebert ^{4, @}

¹ Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
² Department of Medicine, Hematology and Oncology, University of Münster, Münster, Germany
³ Department of Hematology, University Medical Center St. Radboud, Nijmegen, the Netherlands
⁴ Department of Human Genetics, Memorial Sloan–Kettering Cancer Center, Cornell University, New York, New York, USA
⁵ Department of Pharmacology, University of Iowa, Iowa City, Iowa, USA
⁶ Department of Hematology and Oncology, University of Chicago, Chicago, Illinois, USA
⁷ Department of Biochemistry, St. Jude Children's Research Hospital, and Department of Molecular Sciences, University of Tennessee, Memphis, Tennessee, USA

^* C.M.-T., L.v.d.L. and M.H. contributed equally to this study.
^@ Correspondence should be addressed to SW Hiebert.
e-mail:    scott.hiebert@mcmail.vanderbilt.edu

The t(8;21) is one of the most frequent chromosomal translocations associated with acute leukemia. This
translocation creates a fusion protein consisting of the acute myeloid leukemia-1 transcription factor and the
eight-twenty-one corepressor (AML1–ETO), which represses transcription through AML1 (RUNX1) DNA
binding sites and immortalizes hematopoietic progenitor cells. We have identified the p14^ARF tumor suppressor, a mediator of the p53 oncogene checkpoint, as a direct transcriptional target of AML1–ETO. AML1–ETO repressed the p14^ARF promoter and reduced endogenous levels of p14^ARF expression in multiple cell types. In contrast, AML1 stimulated p14^ARF expression and induced phenotypes consistent with cellular senescence. Chromatin immunoprecipitation assays demonstrated that AML1–ETO was specifically bound to the p14^ARFpromoter. In acute myeloid leukemia samples containing the t(8;21), levels of p14^ARFmRNA were markedly lower when compared with other acute myeloid leukemias lacking this translocation. Repression of p14^ARF may explain why p53 is not mutated in t(8;21)-containing leukemias and suggests that p14^ARF is an important tumor suppressor in a large number of human leukemias.

Additional References:

1. Frenster JH, "Electron Microscopic Localization of Acridine Orange Binding to DNA within Human Leukemic Bone Marrow Cells".

2. Frenster JH, "Ultrastructural Probes of Active DNA Sites, and the RNA Activators of DNA".

3. Frenster JH, "Oncogenes as Molecular Targets within Active Chromatin".