Transcriptional upregulation of p21/WAF/Cip1 in myeloid leukemic blasts expressing AML1-ETO.
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.
Berg
Tobias
T
Department of Medicine, Division Hematology/Oncology, University of Freiburg Medical Center, Hugstetter Str. 55, D-79106 Freiburg, Germany.
Fliegauf
Manfred
M
Burger
Jan
J
Staege
Martin S
MS
Liu
Shaohua
S
Martinez
Natalia
N
Heidenreich
Olaf
O
Burdach
Stefan
S
Haferlach
Torsten
T
Werner
Milton H
MH
Lübbert
Michael
M
D001752:Blast Crisis / Q000235:genetics* / Q000473:pathology; D015152:Blotting, Northern; D002874:Chromosome Mapping; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D015854:Up-Regulation; D020741:rho GTP-Binding Proteins / Q000235:genetics*
C493956:CDKN1A protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; C082222:RUNX1T1 protein, human; D014157:Transcription Factors; D020741:rho GTP-Binding Proteins