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Related Collections Neoplasia Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 June 2001, Vol. 97, No. 11, pp. 3648-3650 BRIEF REPORT Expression of nuclear transcription factor interferon consensus sequence binding protein in chronic myeloid leukemia correlates with pretreatment risk features and cytogenetic response to interferon- Manuel Schmidt, Andreas Hochhaus, Andreas Nitsche, Rüdiger Hehlmann, and Andreas Neubauer From the Klinikum der Philipps-Universität Marburg, Zentrum Innere Medizin, Abteilung Hämatologie/Onkologie/Immunologie, Marburg, Germany; III. Medizinische Universitätsklinik, Klinikum Mannheim der Universität Heidelberg, Germany; and Klinik für Innere Medizin m.S. Hamatologie und Onkologie, Charité-Campus Virchow Klinikum, Humboldt Universität, Berlin, Germany.     Abstract Top Abstract Introduction Study design Results and discussion References Recently, it was shown that interferon consensus sequence binding protein (ICSBP), a member of the interferon regulatory factor (IRF) family, has a potential role in chronic myeloid leukemia (CML). Deletion of ICSBP gene in mice leads to a CML-like syndrome and samples from CML patients exhibited impaired ICSBP expression. The present study found that ICSBP expression correlated with risk features determined by Sokal score in untreated CML (P = .007 for high versus low risk). In addition, analyzing ICSBP expression during interferon- (IFN-) therapy in "good" (n = 27) versus "poor" (n = 15) cytogenetic responders, high ICSBP levels were only observed in "good" responders (P = .0002). Together, these data suggest that ICSBP levels are related to initial presentation of CML and the therapeutic response of CML to IFN-, indicating an important role of ICSBP in CML. (Blood. 2001;97:3648-3650) © 2001 by The American Society of Hematology.     Introduction Top Abstract Introduction Study design Results and discussion References Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by bcr-abl gene rearrangement and a typical 3-phase course (chronic, accelerated, and blastic phase) (see Sawyers1 for a review). Treatment with interferon- (IFN-), as monotherapy or in combination with other chemotherapeutic drugs, is frequently used for patients with CML and has prolonged survival.2-6 IFNs are a family of multifunctional cytokines known to regulate cell growth, immune response, and antiviral activity in mammals. They act by activating various downstream signal cascades, which leads to regulation of several transcription factors.7-10 One of these factors is the interferon consensus sequence binding protein (ICSBP), a member of the IFN regulatory factor (IRF) family. ICSBP is known to be regulated by IFNs and subsequently binds to IFN-stimulated response elements (ISRE) in IFN-dependent genes.11,12 ICSBP is preferentially expressed in cells of hematopoietic origin.12,13 ICSBP has been implicated in CML, because ICSBP-knockout mice revealed a granulocytic leukemia similar to CML in humans.14 The deletion of ICSBP gene led also to a blastic transformation that was more frequent in ICSBP/ homozygous compared to ICSBP+/ heterozygous mice.14 Furthermore, a lack of ICSBP expression in CML patients has been described, and stimulation experiments suggested a mechanism of down-regulation.15 To address the question whether ICSBP expression was predictive of the risk profile of untreated patients with CML or later of their cytogenetic response to IFN-, we correlated the transcriptional level of ICSBP in CML with clinical data.     Study design Top Abstract Introduction Study design Results and discussion References Patient samples, RNA isolation, and complementary DNA synthesis Patient samples were taken from patients enrolled in the ongoing German CML trials and the Charité-Campus Virchow Klinikum, Humboldt Universität, Berlin, Germany. Heparinized peripheral blood was drawn after informed consent was obtained. All investigated patients were positive for bcr-abl. RNA was extracted from peripheral blood using the commercially available kits (RNAzol, Paesel, Frankfurt, and RNeasy, QIAGEN, Hilde, Germany). Total RNA (1 µg) was used for complementary DNA (cDNA) synthesis as described previously.15 ICSBP messenger RNA expression analysis Because of the restricted availability of RNA amounts from leukemia patients and the retrospective design of the study, messenger RNA (mRNA) expression analysis was carried out by reverse transcription-polymerase chain reaction (RT-PCR). RT-PCR for ICSBP and -actin was performed as described elsewhere.15 The PCR products were electrophoresed and the gels were photographed. Integrated optical densities (IntOD) were calculated using the ONE-Dscan 1.0' software (Scanalytics, Billerica, MA). Quantitative RT-PCR was performed using a real-time PCR assay with the ABI PRISM 7700 Sequence Detection System (PE Biosystems, Foster City, CA) as described elsewhere.16 In addition to the previously applied primers,15 a labeled ICSBP probe was used (5'-6FAM-TAAGAGCCCAGATTTTGAGGAAG-(TAMRA)-TGACCGG-3'). The -actin was used as reference gene and CT values were then calculated (CT -actin  CT ICSBP).17 Calculation of Sokal score for risk feature discrimination and determination of cytogenetic response to IFN- The Sokal score at diagnosis was calculated as the percentage of peripheral blasts, thrombocytes, size of spleen, and age of the patient at diagnosis as described elsewhere.18 A Sokal score below 0.8 comprises a low risk, from 0.8 to 1.2 an intermediate risk, and above 1.2 a high risk. Cytogenetic response was assessed analyzing at least 10 metaphases and was defined as "good" comprising complete responders (CR, 0% Ph+ metaphases) and partial responders (PR, 1%-34% Ph+ metaphases) or "poor" including patients with a minor (MinR, 35%-94% Ph+ metaphases) or no response (NR, 95%-100% Ph+ metaphases).19 Mean time of IFN- administration was 30.2 months for "good" and 30.1 months for "poor" responders.     Results and discussion Top Abstract Introduction Study design Results and discussion References Pretreatment risk features in CML can be useful for early indication of allogenic transplantation and are commonly determined by Sokal score.18 Because ICSBP expression may play a role in CML, we wanted to study the association of risk profile with ICSBP levels. Thus, we retrospectively analyzed a total of 72 samples from patients with CML in chronic phase without IFN- treatment for their ICSBP expression (median 0.098; range 0.000-0.622). For 33 of these samples the ICSBP level was previously presented.15 Clinical data for calculation of the Sokal score were available for 24 of the 72 CML samples. Correlating the ICSBP expression with the Sokal score, we detected a significant difference of ICSBP expression in the pretreatment risk groups. Patients from the high-risk group had lower ICSBP levels (n = 10; median 0.059; range 0.000-0.273) than patients from the low-risk group (n = 10; median 0.248; range 0.057-0.519) (P = .007) (Figure 1A). Samples with intermediate risk (n = 4) had no significant difference in ICSBP expression to low (P = .374) or high risk (P = .188). Due to the low amounts of samples and an overlap of ICSBP levels in the risk groups, the indicative value of ICSBP expression must be proved with a larger amount of samples. However, we corroborated our data using a real-time PCR assay. Analysis of each 5 randomly selected samples from the high- and low-risk groups yielded a significant difference (data not shown). View larger version (25K): [in this window] [in a new window]   Figure 1. Correlation of ICSBP expression with pretreatment risk groups and cytogenetic response to IFN- in CML patients. (A) The ICSBP level of samples without IFN treatment was analyzed (total n = 72). Twenty-four samples were divided into different risk groups by Sokal score: low risk (n = 10; below 0.8), intermediate risk (n = 4; 0.8-1.2) and high risk (n = 10; above 1.2). The data revealed a correlation of low ICSBP level with high risk (low versus high P = .007; low versus intermediate P = .374; intermediate versus high P = 0.188; Mann-Whitney test). (B) The ICSBP level of samples under IFN- was analyzed (total n = 55). Forty-two samples were divided in groups of "good" (CR/PR; n = 27) and "poor" (MinR/NR; n = 15) responders and revealed a significant difference in ICSBP expression (P = .0002, Mann-Whitney test). We then sought to delineate the implication of ICSBP in CML with the best known prognostic parameter for survival, cytogenetic response to IFN- therapy. Because approximately 70% of the patients exhibit only "poor" cytogenetic response to IFN- therapy, it is useful to identify these resistant patients as early as possible.5 To study the correlation of ICSBP expression and cytogenetic response to IFN-, we first analyzed a total of 55 patients under IFN- for ICSBP expression (median 0.556; range 0.072-1.072). The ICSBP level was significantly higher than in the untreated samples above (P < .0001). This is in keeping with data from sorted B cells, showing that ICSBP expression is impaired in B cells from CML patients without IFN-, whereas B cells from patients under IFN- exhibit a normal ICSBP level (15, data not shown). For 42 patients, complete clinical data were available. They were specified for their cytogenetic response and were divided into groups of 13 CR, 14 PR, 2 MinR, and 13 NR. The samples were preselected for their response, in an attempt to obtain equal amounts of the respective groups. Interestingly, a significant difference in ICSBP levels between CR versus NR or PR versus NR was found (P = .010 or P = .001, respectively). No significant difference between CR and PR itself was detected (P = .297); however, the ICSBP levels from PR were slightly higher than in CR (Table 1). By analyzing combined groups of "good" (n = 27; CR/PR, 0%-34% Ph+) and "poor" responders (n = 15; MinR/NR, 35%-100% Ph+), we detected an even more striking correlation of "good" response with high ICSBP expression (median 0.715; range 0.132-1.072) and "poor" response with low ICSBP level (median 0.325; range 0.072-0.961) (P = .0002; Figure 1B). Again, we corroborated our data using the real-time PCR assay. Analysis of each 5 randomly selected samples from "good" and "poor" responders gave also a significant difference (data not shown).                                View this table: [in this window] [in a new window]   Table 1. Interferon consensus sequence binding protein levels in chronic myeloid leukemia samples from different responders to interferon- therapy Interestingly, analyzing 15 samples during follow-up, the initial ICSBP level before IFN- treatment of patients becoming "good" responders was significantly higher than that of "poor" responders (data not shown). Our results suggest that ICSBP expression in untreated CML patients indicates classification into different risk groups. In addition, cytogenetic response to IFN- therapy in CML correlates to ICSBP expression, leading to normal mRNA levels only in "good" responders. These data suggest a possible usage of ICSBP levels for deciding therapy strategies in CML, maybe by early determination of cytogenetic response to IFN-, and thus enabling patients to receive a faster allogeneic stem cell transplantation. Current studies with mice support the conclusion of the importance of ICSBP in CML therapy. It was shown that mice transplanted with bcr-abl-transfected bone marrow cells developed a myeloproliferative disease resembling CML.20,21 Interestingly, mice transplanted with bone marrow cells coexpressing ICSBP and bcr-abl showed prolonged survival in contrast to the mice transplanted with cells expressing bcr-abl alone, indicating a protective role of ICSBP against bcr-abl.21 Taken together, the data presented here strongly suggest that lack of ICSBP may be involved in chronic myeloid leukemogenesis and an increase of ICSBP may have an important role in the therapeutic effect of IFN-. Further prospective studies are needed to evaluate the detailed role of ICSBP in CML and a possible use as marker for prognosis or therapy or seperately as a target of gene therapy.     Acknowledgments We thank Prof D. Huhn for his help throughout the study. We are grateful to the patients, physicians, and cytogeneticists participating in the German CML trials for sending samples and providing clinical and cytogenetic data.     Footnotes Submitted July 26, 2000; accepted January 24, 2001. Supported in part by grants from the Deutsche Forschungsgemeinschaft (to A.N.), the H.W. and J. Hector Stiftung (to M.S. and A.N.), the Deutsche Jose-Carreras-Leukämie-Stiftung e.V. (to M.S., A.N., and A.H.) and the A. and U. Kuhlemann-Stiftung (to M.S. and A.N.). The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Andreas Neubauer, Klinikum der Philipps-Universität Marburg, Zenrum Innere Medizin, Abteilung Hämatologie/Onkologie/Immunologie, Baldingerstrasse, 35043 Marburg, Germany; e-mail: neubauer{at}mailer.uni-marburg.de.     References Top Abstract Introduction Study design Results and discussion References 1. Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999;40:1330-1340. 2. Tura S, Baccarani M, Zuffa E, et al. Interferon alpha-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N Engl J Med. 1994;330:820-825[Abstract/Free Full Text]. 3. Hehlmann R, Heimpel H, Hasford J, et al. Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. The German CML Study Group. Blood. 1994;84:4064-4077[Abstract/Free Full Text]. 4. Allan NC, Richards SM, Shepherd PCA. UK Medical Research Council randomized multicentre trial of interferon-alpha n1 for chronic myeloid leukemia: improved survival irrespective of cytogenetic response. Lancet. 1995;345:1392-1397[CrossRef][Medline] [Order article via Infotrieve]. 5. Kantarjian H, O'Brien S, Anderlini P, Talpaz M. Treatment of myelogenous leukemia: current status and investigational options. Blood. 1996;87:3069-3081[Free Full Text]. 6. Guilhot F, Chastang C, Michallet M, et al. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group. N Engl J Med. 1997;337:223-229[Abstract/Free Full Text]. 7. Petska S, Langer JA, Zoon KC, Samuel CE. Interferons and their actions. Annu Rev Biochem. 1987;56:727-777[CrossRef][Medline] [Order article via Infotrieve]. 8. Tanaka N, Taniguchi T. Cytokine gene regulation: regulatory cis elements and DNA binding factors involved in the interferon system. Adv Immunol. 1992;52:263-281[Medline] [Order article via Infotrieve]. 9. Schindler C, Darnell JE Jr. Transcriptional responses to polypeptide ligands: the Jak-STAT pathway. Annu Rev Biochem. 1995;64:621-651[Medline] [Order article via Infotrieve]. 10. Darnell JE Jr. STATs and gene regulation. Science. 1997;277:1630-1635[Abstract/Free Full Text]. 11. Driggers PH, Ennist DL, Gleason SL, et al. An interferon -regulated protein that binds the interferon-inducible enhancer-element of major histocompatibility complex class I genes. Proc Natl Acad Sci U S A. 1990;87:3743-3747[Abstract/Free Full Text]. 12. Weisz A, Marx P, Sharf R, et al. Human interferon consensus sequence binding protein is a negative regulator of enhancer elements common to interferon-inducible genes. J Biol Chem. 1992;267:25589-25596[Abstract/Free Full Text]. 13. Nelson N, Kanno Y, Hong C, et al. Expression of interferon regulatory factor family proteins in lymphocytes: induction of Stat 1 and ICSBP expression by T cell activation. J Immunol. 1996;156:3711-3720[Abstract]. 14. Holtschke T, Löhler J, Kanno Y, et al. Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Cell. 1996;87:307-317[CrossRef][Medline] [Order article via Infotrieve]. 15. Schmidt M, Nagel S, Proba J, et al. Lack of interferon consensus sequence binding protein (ICSBP) transcripts in human myeloid leukemias. Blood. 1998;91:22-29[Abstract/Free Full Text]. 16. Nitsche A, Steuer N, Schmidt CA, Landt O, Siegert W. Different real-time PCR formats compared for the quantitative detection of human cytomegalovirus DNA. Clin Chem. 1999;45:1932-1937[Abstract/Free Full Text]. 17. Kreuzer KA, Lass U, Landt O, et al. Highly sensitive and specific fluorescence reverse transcription-PCR assay for the pseudogene-free detection of beta-actin transcripts as quantitative reference. Clin Chem. 1999;45:297-300[Free Full Text]. 18. Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood. 1984;63:789-799[Abstract/Free Full Text]. 19. Hochhaus A, Yan XH, Willer A, et al. Expression of interferon regulatory factor (IRF) genes and response to interferon- in chronic myeloid leukemia. Leukemia. 1997;11:933-939[CrossRef][Medline] [Order article via Infotrieve]. 20. Zhang X, Ren R. Bcr-abl efficiently induces a myeloproliferative disease and production of excess interleukin-3 and granulocyte-macrophage colony-stimulating factor in mice: a novel model for chronic myelogenous leukemia. Blood. 1998;92:3829-3840[Abstract/Free Full Text]. 21. Hao SX, Ren R. Expression of interferon consensus sequence binding protein (ICSBP) is downregulated in bcr-abl-induced murine chronic myelogenous leukemia-like disease, and forced coexpression of ICSBP inhibits bcr-abl-induced myeloproliferative disorder. Mol Cell Biol. 2000;20:1149-1161[Abstract/Free Full Text]. © 2001 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. Saberwal, E. Horvath, L. Hu, C. Zhu, E. Hjort, and E. A. Eklund The Interferon Consensus Sequence Binding Protein (ICSBP/IRF8) Activates Transcription of the FANCF Gene during Myeloid Differentiation J. Biol. Chem., November 27, 2009; 284(48): 33242 - 33254. [Abstract] [Full Text] [PDF] J. Koenigsmann, C. Rudolph, S. Sander, O. Kershaw, A. D. Gruber, L. Bullinger, B. Schlegelberger, and D. 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[Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Schmidt, M. Articles by Neubauer, A. Search for Related Content PubMed PubMed Citation Articles by Schmidt, M. Articles by Neubauer, A. Related Collections Neoplasia Brief Reports Social Bookmarking                   What's this?

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