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Published on: March 24, 2015
Lack of interferon consensus sequence binding protein (ICSBP) transcripts in human myeloid leukemias
1Medizinische Klinik I, Universit-atsklinik Carl Gustav Carus, Dresden, Germany.
Insights
Interferon consensus sequence binding protein (ICSBP) is often lacking in human myeloid leukemias, suggesting its deficiency plays a role in cancer development. Restoring ICSBP levels, even during treatment, shows promise for leukemia therapy.
Area of Science:
- Molecular Biology
- Hematology
- Oncology
Background:
- Interferon consensus sequence binding protein (ICSBP) is an interferon regulatory factor (IRF) family member.
- ICSBP regulates interferon-dependent gene expression via DNA binding.
- ICSBP deficiency in mice causes hematologic alterations resembling chronic myelogenous leukemia (CML).
Purpose of the Study:
- To investigate the role of ICSBP in human myeloid leukemias.
- To determine ICSBP-mRNA expression levels in CML and acute myeloid leukemia (AML) patients.
- To assess the inducibility of ICSBP in leukemic cells.
Main Methods:
- Quantitative analysis of ICSBP-mRNA in patient samples (CML, AML, normal volunteers).
- Analysis of ICSBP expression in sorted B cells.
- Ex vivo induction of ICSBP using interferon-gamma (IFN-gamma).
- In vivo analysis of ICSBP during interferon-alpha (IFN-alpha) treatment.
- Stable transfection of K-562 cell line with ICSBP.
Main Results:
- ICSBP-mRNA expression is significantly impaired in CML (79%) and AML (66%) patients compared to normal volunteers (6%).
- ICSBP deficiency was observed in sorted B cells from CML patients.
- Ex vivo IFN-gamma treatment induced ICSBP transcripts in primary CML cells.
- In vivo IFN-alpha treatment induced ICSBP-mRNA in most CML patients, but levels decreased with disease progression.
- Stable ICSBP transfection did not alter bcr-abl expression in vitro, but an inverse correlation was noted in vivo in some patients.
Conclusions:
- Reduced ICSBP expression is a common feature of human myeloid leukemias.
- ICSBP deficiency may contribute to myeloid leukemogenesis.
- ICSBP is inducible in leukemic cells, suggesting potential therapeutic strategies.
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.
