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

• Published in: Haematologica (Roma) 2008-11, Vol.93 (11), p.1728-1733
• Main Authors: Berg, Tobias, Fliegauf, Manfred, Burger, Jan, Staege, Martin S, Liu, Shaohua, Martinez, Natalia, Heidenreich, Olaf, Burdach, Stefan, Haferlach, Torsten, Werner, Milton H, Lubbert, Michael
• Format: Article
• Language: English
• Subjects: Blast Crisis - genetics; Blast Crisis - pathology; Blotting, Northern; Chromosome Mapping; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 8; Core Binding Factor Alpha 2 Subunit - genetics; Cyclin-Dependent Kinase Inhibitor p21 - genetics; DNA-Binding Proteins - genetics; Flow Cytometry; Gene Expression Regulation, Neoplastic; Genes, p53; Humans; Leukemia, Myeloid - genetics; Leukemia, Myeloid - pathology; Mutation; Oligonucleotide Array Sequence Analysis; Proto-Oncogene Proteins - genetics; rho GTP-Binding Proteins - genetics; RUNX1 Translocation Partner 1 Protein; Transcription Factors - genetics; Transcription, Genetic; Translocation, Genetic; Up-Regulation
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.13044

1 Division of 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 Division of Pediatric 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 and 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.