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ICSBP promoter methylation in myelodysplastic syndromes and acute myeloid leukaemia

Leukemia volume 25, pages 1202–1207 (2011)Cite this article

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Interferon consensus sequence-binding protein (ICSBP) was first described as a negative regulator of interferon-inducible genes, implying an important role in interferon (IFN)γ signalling and immune response.1, 2 Later, ICSBP-deficient mice were shown to develop a disease resembling human chronic myeloid leukaemia,3, 4 suggesting a tumour suppressor function of ICSBP. ICSBP functions as a molecular switch factor directing the differentiation of bi-potential myeloid precursors toward the monocytic lineage,5 possibly by forming heterodimeric complexes with PU.1.6 Moreover, ICSBP has pro-apoptotic properties,7 and modulates proliferation of leukaemic cells, requiring the chemokines CCL6 and CCL9.8, 9 Despite these important roles of ICSBP shown in the differentiation of haematopoietic cells, relatively less is known about its inactivation in human myeloid malignancies. Patients with chronic myeloid leukaemia and acute myeloid leukaemia (AML) show reduced ICSBP-mRNA expression.10 Furthermore, reduced ICSBP expression correlates with poor cytogenetic response to IFNα treatment.11 Gene expression profiling of CD34+ haematopoietic stem/progenitor cells revealed that therapy-related AML with loss of chromosome 5 or deletion of 5q (−5/del(5q)), in addition to upregulation of growth-promoting genes, had no expression of ICSBP.12 Using a novel approach to determine the methylation status of candidate tumour suppressor genes called methyl-binding (MB)-PCR, the ICSBP gene was identified as a target of hypermethylation in AML.13

To obtain a first estimation of whether and to what extent ICSBP transcription is downregulated and whether there is an association between downregulation of ICSBP and recurrent cytogenetic aberrations of myelodysplastic syndrome (MDS) and AML, we screened the PubMed GEO database (http://www.ncbi.nlm.gov/geo/accession number GSE425/8653, Supplementary Figure S1a and b).14, 15 By gene-expression data mining, a significant downregulation of ICSBP in AML with t(15;17) and with t(8;21), and a tendency of ICSBP downregulation in –7/del(7q) was found (Supplementary Figure S1c). Furthermore, an ICSBP downregulation was published for therapy-induced AML with –5/del(5q).12 To substantiate these findings, we investigated a cohort of 100 patients with myeloid malignancies that had been characterized cytogenetically (Supplementary Table S3). Informed consent was obtained according to the Declaration of Helsinki. The study was approved by the Institutional Ethics Committee of Hannover Medical School under No. 2899 (26.02.2002).

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Acknowledgements

We thank Friederike Grundstedt and Sabine Schreek for their excellent technical assistance. Further, we thank Gillian Teicke for editing the manuscript. This study was supported by grants from the BMBF (BMFS-Netzwerk ‘Chromosomal instability as a basic genetic mechanism of tumorigenesis in congenital bone marrow failure syndromes’ 01 GM 0618). NO receives a fellowship from the Deutsche José Carreras Leukämie-Stiftung eV.

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Authors and Affiliations

  1. Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany

    N Otto, G Manukjan, G Göhring, W Hofmann, J Chacon Luna, B Schlegelberger & D Steinemann

  2. Institute for Biometry, Hannover Medical School, Hannover, Germany

    R Scherer

  3. Institute of Pathology, Hannover Medical School, Hannover, Germany

    U Lehmann

  4. Department of Haematology, Haemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    A Ganser

  5. Centre for Paediatrics and Adolescent Medicine and Dermatology, Hannover Medical School, Hannover, Germany

    K Welte

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Correspondence to N Otto.

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Otto, N., Manukjan, G., Göhring, G. et al. ICSBP promoter methylation in myelodysplastic syndromes and acute myeloid leukaemia. Leukemia 25, 1202–1207 (2011). https://doi.org/10.1038/leu.2011.61

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