Wilms' tumor gene 1 protein represses the expression of the tumor suppressor interferon regulatory factor 8 in human hematopoietic progenitors and in leukemic cells.
Wilms' tumor gene 1 (WT1) is a transcription factor involved in developmental processes. In adult hematopoiesis, only a small portion of early progenitor cells express WT1, whereas most leukemias show persistently high levels, suggesting an oncogenic role. We have previously characterized oncogenic BCR/ABL1 tyrosine kinase signaling pathways for increased WT1 expression. In this study, we show that overexpression of BCR/ABL1 in CD34+ progenitor cells leads to reduced expression of interferon regulatory factor 8 (IRF8), in addition to increased WT1 expression. Interestingly, IRF8 is known as a tumor suppressor in some leukemias and we investigated whether WT1 might repress IRF8 expression. When analyzed in four leukemia mRNA expression data sets, WT1 and IRF8 were anticorrelated. Upon overexpression in CD34+ progenitors, as well as in U937 cells, WT1 strongly downregulated IRF8 expression. All four major WT1 splice variants induced repression, but not the zinc-finger-deleted WT1 mutant, indicating dependence on DNA binding. A reporter construct with the IRF8 promoter was repressed by WT1, dependent on a putative WT1-response element. Binding of WT1 to the IRF8 promoter was demonstrated by chromatin immunoprecipitation. Our results identify IRF8 as a direct target gene for WT1 and provide a possible mechanism for oncogenic effects of WT1 in leukemia.
Department of Hematology, Lund University, Lund, Sweden.
K
K
Vidovic
E
E
Svensson
B
B
Nilsson
B
B
Thuresson
T
T
Olofsson
A
A
Lennartsson
U
U
Gullberg
D018952:Antigens, CD34 / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D015536:Down-Regulation; D005312:Fetal Blood; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D020298:U937 Cells; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism*; D000099185:Interferon Regulatory Factor-8
D018952:Antigens, CD34; D014408:Biomarkers, Tumor; D016044:Fusion Proteins, bcr-abl; D050835:Interferon Regulatory Factors; D012333:RNA, Messenger; D025721:WT1 Proteins; D000099185:Interferon Regulatory Factor-8