The prolyl‐hydroxylase EGLN3 and not EGLN1 is inactivated by methylation in plasma cell neoplasia |
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| Authors: | Eleftheria Hatzimichael Aggeliki Dasoula Reshma Shah Nelofer Syed Alexandra Papoudou‐Bai Helen M. Coley George Dranitsaris Konstantinos L. Bourantas Justin Stebbing Tim Crook |
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| Affiliation: | 1. Department of Haematology, Medical School of Ioannina, University of Ioannina, Ioannina, Greece;2. Laboratory of Cancer Genetics and Epigenetics, Breakthrough Breast Cancer, Institute of Cancer Research, London, UK;3. Department of Pathology, Medical School of Ioannina, University of Ioannina, Ioannina, Greece;4. Postgraduate Medical School, University of Surrey, Guildford, Surrey, UK;5. Department of Medical Oncology, Princess Margaret Hospital, Toronto, ON, Canada;6. Department of Medical Oncology, Imperial College, Charing Cross Hospital, London, UK |
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| Abstract: | EGLN1 and EGLN3 are members of the egg‐laying‐defective 9 (EglN) prolyl‐hydroxylases which during normoxia catalyse hydroxylation of the hypoxia‐inducible factor (HIF)‐1α, thereby promoting its ubiquitination by a complex containing the von Hippel–Lindau (VHL) tumour suppressor. EGLN3 also has pro‐apoptotic activity in some cell types. Analyses of a well‐characterised series of cases of plasma cell dyscrasias, including multiple myeloma (MM), Waldenström’s macroglobulinaemia (WM) and monoclonal gammopathy of undetermined significance (MGUS) surprisingly demonstrated that the CpG island of EGLN3, and not EGLN1, is frequently methylated in these disorders. Multiple myeloma patients with a methylated EGLN3 promoter showed trends towards an increased risk of death, bone lytic lesions, anaemia, advanced stage of disease and the presence of extramedullary disease. Those individuals with methylation in the EGLN3 CpG island also had significantly lower albumin levels. These data suggest that the prolyl‐hydroxylases may be a novel class of potential tumour suppressors in plasma cell neoplasia that warrant further investigation with regard to their potential utility as biomarkers. Moreover, we observed that EGLN3 is also methylated at high frequency in B‐cell lymphoma subtypes, implying that loss of EGLN3 is an important epigenetic event not only in plasma cell neoplasias but also in B‐cell neoplasias. |
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| Keywords: | multiple myeloma plasma cell neoplasia methylation EGLN1 EGLN3 prolyl‐hydroxylase |
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