title: Lack of interferon consensus sequence binding protein (ICSBP) transcripts in human myeloid leukemias.
abstract: Interferon consensus sequence binding protein (ICSBP) was first identified as a transcription factor of the interferon (IFN) regulatory factor family (IRF) which regulates expression of IFN-dependent genes by binding to DNA at specific sites, IFN-stimulated responsive elements. Analysis of ICSBP-deficient mice showed hematologic alterations similar to chronic myelogenous leukemia (CML) in humans and suggested a novel role for ICSBP in regulating proliferation and differentiation of hematopoietic progenitor cells. Here we show that ICSBP-mRNA expression is impaired in human myeloid leukemias: 27 of 34 CML patients (79%) and 21 of 32 patients with acute myeloid leukemia (AML) (66%) showed very low or absent transcript numbers of ICSBP. In contrast, only 2 of 33 normal volunteers (6%) showed low transcription of ICSBP (P < . 0001 both for CML and AML values). The lack of expression was not associated with lack of lymphatic cells, which normally have been shown to express ICSBP at the highest level. More detailed analysis showed an absence of ICSBP-mRNA also in sorted B cells derived from CML patients. To analyze whether ICSBP may be induced in leukemic cells, ex vivo experiments using a known inducer of ICSBP, IFN-gamma, were performed. Ex vivo treatment of primary CML cells using IFN-gamma resulted in induction of ICSBP transcripts. Furthermore, samples of CML patients during IFN-alpha treatment were analyzed. In 11 of 12 CML patients ICSBP-mRNA was inducible upon in vivo treatment with IFN-alpha, but decreased with progression of CML. Stable transfection of K-562 cell line with ICSBP led to no difference in bcr-abl expression in vitro, although two patients showed an inverse correlation between bcr-abl and ICSBP in vivo. These data suggest that lack of ICSBP may have an important role also in human myeloid leukemogenesis.
authors.affiliation: Medizinische Klinik I, Universit-atsklinik Carl Gustav Carus, Dresden, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schmidt
authors.forename: S
authors.initials: S
authors.lastname: Nagel
authors.forename: J
authors.initials: J
authors.lastname: Proba
authors.forename: C
authors.initials: C
authors.lastname: Thiede
authors.forename: M
authors.initials: M
authors.lastname: Ritter
authors.forename: J F
authors.initials: JF
authors.lastname: Waring
authors.forename: F
authors.initials: F
authors.lastname: Rosenbauer
authors.forename: D
authors.initials: D
authors.lastname: Huhn
authors.forename: B
authors.initials: B
authors.lastname: Wittig
authors.forename: I
authors.initials: I
authors.lastname: Horak
authors.forename: A
authors.initials: A
authors.lastname: Neubauer
mesh_terms: D002908:Chronic Disease; D016384:Consensus Sequence; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D005822:Genetic Vectors; D006801:Humans; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D000099185:Interferon Regulatory Factor-8
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D016044:Fusion Proteins, bcr-abl; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D012097:Repressor Proteins; D000099185:Interferon Regulatory Factor-8