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Tumor Gene 1 Protein Represses the Expression of the Tumor Suppressor Interferon Regulatory Factor 8 in Human Hematopoietic Progenitors and in Leukemic Cells

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Tumor Gene 1 Protein Represses the Expression of the Tumor Suppressor Interferon Regulatory Factor 8 in Human Hematopoietic Progenitors and in Leukemic Cells Leukemia (2010) 24, 992–1000 & 2010 Macmillan Publishers Limited All rights reserved 0887-6924/10 $32.00 www.nature.com/leu ORIGINAL ARTICLE Wilms’ tumor gene 1 protein represses the expression of the tumor suppressor interferon regulatory factor 8 in human hematopoietic progenitors and in leukemic cells K Vidovic1, E Svensson1, B Nilsson2, B Thuresson1, T Olofsson1, A Lennartsson3 and U Gullberg1 1Department of Hematology, Lund University, Lund, Sweden; 2Cancer Program, Broad Institute, Cambridge, MA, USA and 3Department of Biosciences and Medical Nutrition, Karolinska Institutet, Huddinge, Sweden Wilms’ tumor gene 1 (WT1) is a transcription factor involved in often interferes with differentiation.15–17 Thus, a large amount of developmental processes. In adult hematopoiesis, only a small data indicates a leukemogenic role of WT1. Despite the fact that portion of early progenitor cells express WT1, whereas most some target genes of WT1 have been suggested (reviewed leukemias show persistently high levels, suggesting an onco- 18 genic role. We have previously characterized oncogenic BCR/ in Yang et al. ), the mechanisms through which WT1 exerts its ABL1 tyrosine kinase signaling pathways for increased WT1 leukemogenic effects remain unclear. expression. In this study, we show that overexpression of BCR/ Interferon regulatory factor 8 (IRF8), also designated ICSBP ABL1 in CD34 þ progenitor cells leads to reduced expression (interferon consensus sequence-binding protein), belongs to the of interferon regulatory factor 8 (IRF8), in addition to increased IRF family of transcription factors and is normally expressed WT1 expression. Interestingly, IRF8 is known as a tumor suppressor in some leukemias and we investigated whether in hematopoietic cells, including monocytes, macrophages WT1 might repress IRF8 expression. When analyzed in four and subsets of lymphocytes, showing inducibility by a- and 19 leukemia mRNA expression data sets, WT1 and IRF8 were g-interferon (reviewed in Tamura et al ). In late myeloid anticorrelated. Upon overexpression in CD34 þ progenitors, as differentiation, IRF8 participates in the commitment to macro- well as in U937 cells, WT1 strongly downregulated IRF8 phage differentiation and is important for the function of mature expression. All four major WT1 splice variants induced repres- macrophages, and several IRF8 target genes in developing sion, but not the zinc-finger-deleted WT1 mutant, indicating 19 dependence on DNA binding. A reporter construct with the IRF8 macrophages have been identified. In contrast to the almost promoter was repressed by WT1, dependent on a putative WT1- ubiquitously high expression of WT1 in leukemias, the expres- 20 response element. Binding of WT1 to the IRF8 promoter was sion of IRF8 is very low or absent in most leukemias. demonstrated by chromatin immunoprecipitation. Our results Interestingly, elimination of IRF8 in transgenic mice results identify IRF8 as a direct target gene for WT1 and provide a in a systemic expansion of granulocytes with later transition possible mechanism for oncogenic effects of WT1 in leukemia. into blast crisis, a development very similar to human chronic Leukemia (2010) 24, 992–1000; doi:10.1038/leu.2010.33; 21 published online 18 March 2010 myeloid leukemia (CML). Similar hematopathological distur- Keywords: WT1; IRF8; promoter; repression bances, although in milder forms, were also observed after heterozygous elimination of IRF8, indicating haploid insuffi- ciency of IRF8.21 The importance of reduced levels of IRF8 in the pathogenesis of CML is further underscored by the observation that forced expression of IRF8 counteracts the BCR/ Introduction ABL1-induced leukemic phenotype in vivo22 and in vitro.23,24 Besides its association with the development of CML, a role Wilms’ tumor gene 1 (WT1) encodes a DNA-binding zinc- of IRF8 is also implicated in acute leukemogenesis; in murine finger transcription factor necessary for the development models for acute leukemia, IRF8 acts as a tumor suppressor, of various organs and structures in the fetus (reviewed in 1 2 the loss of which cooperates with leukemogenic fusion genes Lee and Haber and in Scharnhorst et al. ). Expression of WT1 in NUP98-TOP1 or AML1-ETO,25,26 with the oncogenic SHP2 a small fraction of early progenitor cells in human and murine 27 28 3–8 tyrosine phosphatase and with loss of neurofibromin 1. adult hematopoiesis, as well as analysis of WT1-deficient Antiproliferative mechanisms downstream of IRF8 may include murine progenitors showing impaired reconstitution of hemato- 29 9 upregulation of p15INK4b, but the mechanism by which the poiesis in vivo, indicate a role for WT1 in maintaining proli- level of IRF8 is regulated within the context of leukemia is feration and/or survival of hematopoietic cells. Consistent with unknown. this notion, overexpression of WT1 alone in myeloid progenitors 10 In this study, we report that the WT1 protein, frequently induced a myeloproliferative-like disorder in mice, and overexpressed in leukemia, can directly repress transcription coexpression of WT1 and the fusion protein AML1-ETO resulted 10 of the IRF8 gene, thus providing a novel mechanism by which in a rapid development of acute leukemia, lending further WT1 might contribute to leukemogenesis. support for the role of WT1 as an oncogene in leukemia. High levels of WT1 are detected in most cases of chronic and acute human leukemia,11–14 as well as in most leukemic Materials and methods cell lines. Whereas endogenous WT1 is downregulated after induced differentiation of cell lines, overexpression of WT1 Cell culture Umbilical cord blood was, after ethical approval and informed Correspondence: Dr U Gullberg, Department of Hematology, Lund consent, collected from mothers giving birth to normal full-term University, BMC, C14, Klinikgatan 28, Lund SE-221 84, Sweden. E-mail: [email protected] infants, from which mononuclear cells were isolated by Received 24 September 2009; revised 21 December 2009; accepted separation on Lymphoprep (Nycomed Pharma, Oslo, Norway), 7 January 2010; published online 18 March 2010 and CD34 þ cells were enriched by labeling with magnetic WT1 protein represses IRF8 K Vidovic et al 993 beads (CD34 Progenitor Cell Isolation Kit, Miltenyi Biotec, Bisulfite sequencing Bergisch-Gladbach, Germany) according to the manufacturer’s DNA-methylation status of the IRF8 promoter in U937 cells and instructions. CD34 þ cell purity was always 490% as deter- CD34 þ cells was analyzed by bisulfite sequencing using the EZ mined by flow cytometry. 293T/17 (American Type Culture DNA Methylation-Direct kit (Zymo Research, Orange, CA, USA) Collection, Manassas, VA, USA) cells were maintained in according to the manufacturer’s protocol, using ZymoTaq DNA Dulbecco’s modified Eagle’s medium supplemented with 10% polymerase (Zymo Research) in the PCR reaction. The conver- fetal calf serum. U937 cells were obtained from the German sion rate was 494%. A 361-bp sequence in the IRF8 promoter Collection of Microorganisms and Cell Cultures (Braunschweig, was sequenced after PCR amplification with the following Germany). The CML cell lines KU812, LAMA-84 and JK-1 cells primer pair: 50-TAGTGGTTTTTTTTGAAGTTGGG-30 and 50-TA were kindly donated by Dr Thoas Fioretos (Clinical Genetics, CAAAAAAACTTTCCCAAAAATTC-30 amplifying À564 to À278 Lund University, Lund, Sweden). Both U937 and CML cell lines of the IRF8 promoter. The TOPO TA Cloning Kit (Invitrogen, were maintained in RPMI 1640 supplemented with 10% fetal Carlsbad, CA, USA) and the BigDye Terminator v1.1 Sequencing calf serum. Kit (Applied Biosystems) with M13 forward and M13 reverse primers were used for cloning and sequencing, respectively. RNA isolation, reverse transcription and RT-qPCR To analyze the expression of WT1 and IRF8 mRNA, total RNA Cloning and site-directed mutagenesis of IRF8 promoter was isolated using the RNeasy Mini Kit or RNeasy Micro Kit Cloning of human IRF8 promoter genomic DNA was performed according to the manufacturer’s protocol (Qiagen Gmbh, Hilden using the GC-Rich PCR Kit (Roche Diagnostics Gmbh, Germany). A total of 200 ng of total RNA was reverse transcribed Mannheim, Germany). The cloned promotor construct con- using High-Capacity cDNA Reverse Transcription Kit (Applied tained 970 bp upstream of the transcription start and 74 bp Biosystems Inc., Foster City, CA, USA) with random hexamer downstream of the transcription start. The following primers primers according to the manufacturer’s instructions. In some were used for cloning: Sense: outer 50-GGTCCCTGAAAAGCTCAACGCA-30 experiments with BCR/ABL1-transduced CD34 þ cells, 500 0 0 GFP þ cells were sorted directly (by a FACS Aria, BD, Franklin andnested5-TATACGCGTGCCCCCATGTGTGATTCTCTAC-3 ; antisense: outer 50-GGGGACATTACGGTAGGTAGTTCC-30 Lakes, NJ, USA) into PCR tubes containing cell lysis buffer, after 0 0 which reverse transcription (RT) reaction was performed using the and nested 5 -GATAAGCTTCCGCCCACTGTGCCTACCT-3 . Sensiscript RT kit (Qiagen) as described elsewhere.30 Quantitative The PCR product was cloned into the pGL3 Basic firefly PCR (qPCR) was carried out using TaqMan probe-based chemistry luciferase reporter vector (MluI/HindIII) (Promega, Madison, (Applied Biosystems). The probes for the WT1 (Hs00240913_m1), WI, USA). Core nucleotides of a potential WT1-binding site in IRF1 (Hs00971960_m1), IRF4 (Hs00277069_m1) IRF8 the promoter were mutated by PCR: À45/À38 CCCCA were (Hs00175238_m1), ISG15 (interferon-stimulated gene 15) mutated to AATAT. (Hs01921425_s1) and the endogenous
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