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Transcriptional upregulation of p21/WAF/Cip1 in myeloid leukemic blasts expressing AML1-ETO

¹ Div. Hematology/Oncology, University of Freiburg Medical Center, Freiburg, Germany
² Dept. Pediatrics, University of Freiburg Medical Center, Freiburg, Germany
³ Dept. of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
⁴ Div. Ped. Hematology/Oncology, Martin-Luther-University Halle, Halle, Germany
⁵ Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY, USA
⁶ Institute of Cell Biology, Department of Molecular Biology, Eberhard Karls University Tuebingen, Tuebingen, Germany
⁷ Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
⁸ Pediatric Oncology Center and Department of Pediatrics, Munich University of Technology, Munich, Germany
⁹ MLL Munich Leukemia Laboratory, Munich, Germany
¹⁰ Celtaxsys, ATDC Biosciences Center, Atlanta, GA, USA

Correspondence: Michael Lübbert, MD PhD, Department of Medicine, Division Hematology/Oncology, University of Freiburg Medical Center, Hugstetter Str. 55, D-79106 Freiburg, Germany. E-mail:luebbert{at}mm11.ukl.uni-freiburg.de

ABSTRACT

An inducible model for conditional expression of AML1-ETO in myeloid U-937 cells was generated previously to determine cellular effects of AML1-ETO and to identify target genes. Induction of AML1-ETO expression in U-937 resulted in reduced cell growth, G1 arrest and apoptosis. Microarray analysis showed more genes up-regulated than down-regulated (180 vs. 69). Clustering of AML1-ETO-positive and -negative cell lines was possible based on these differentially expressed genes. p21/WAF/Cip1 (CDKN1A) was up-regulated 4.6-fold upon induction of AML1-ETO which was confirmed in additional experiments. Knock-down of AML1-ETO by siRNA could reduce p21/WAF/Cip1 expression in Kasumi-1 cells. mRNA expression analysis of p21/WAF/Cip1 in a large cohort of acute myeloid leukemia patients demonstrated a significantly higher expression in AML1-ETO-positive leukemia. The increased expression of p21/WAF/Cip1 in primary leukemic blasts suggests that elevated p21/WAF/Cip1 levels may contribute to specific features observed in AML1-ETO positive leukemia.

Key words: cell cycle, acute myeloid leukemia, chromosomal translocation.