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Zheng Zhang,
Xiao Li,
Juan Guo,
Feng Xu,
Qi He,
Youshan Zhao, Yujuan Yang,
Shucheng Gu,
Yan Zhang,
Lingyun Wu,
Chunkang Chang
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ABSTRACT: INTRODUCTION: Lower risk myelodysplastic syndromes (MDSs) are characterised by increased apoptosis of haematopoietic cells in the bone marrow (BM). The mechanism driving this excessive apoptosis involves multiple immune molecules, including inflammatory cytokines such as interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α) and interleukins (ILs). Interleukin-17(IL-17) is the hallmark cytokine produced by CD4+ Th17 cells, and IL-17 mediates activation of the adaptive T cell response, inducing an inflammatory cytokine environment. However, little is known about the role of IL-17 in MDS-associated immune dysfunction. METHODS: A total of 47 patients with myelodysplastic syndromes were enrolled in this study, and the levels of IL-17 and IL-17 receptor (IL-17R) in BM mononuclear cells (BMNCs) were detected by real-time polymerase chain reaction (RQ-PCR) and enzyme-linked immunosorbent assay (ELISA). Then, BMNCs were stimulated with recombinant human IL-17 (rhIL-17), and flow cytometry was used to analyse the production of IFN-γ and TNF-α by CD4+ and CD8+ T lymphocytes from lower risk MDS patients. Characterisation of IL-17 expression in patients with the HLA-DR15 allele or hypocellularity was also performed. RESULTS: mRNA levels for both IL-17 and the IL-17R subunits in BMNCs and for IL-17 in the BM and plasma were higher in patients with lower risk MDS as compared to patients with higher risk MDS and normal controls. The production of IFN-γ and TNF-α by CD4+ and CD8+ T lymphocytes from lower risk MDS patients could be enhanced by recombinant human IL-17 (rhIL-17) treatment. Furthermore, increased IL-17 expression was associated with more severe anaemia in MDS patients. CONCLUSION: Elevated IL-17 levels and IL-17-induced IFN-γ and TNF-α overproduction may be involved in the pathogenesis of lower risk MDS. © 2013 John Wiley & Sons A/S.
European Journal Of Haematology 01/2013; · 2.61 Impact Factor
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ABSTRACT: BLU methylation status was investigated in bone marrow mononuclear cells from newly diagnosed myelodysplastic syndrome (MDS) patients and patients who received 5-aza-2'-deoxycytidine (decitabine) treatment so as to determine the effect of BLU in the pathogenesis of MDS.
Methylation-specific polymerase chain reaction and bisulfite sequencing were used to evaluate the methylation status of the promoter region of the BLU gene. BLU expression was investigated by using quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot analysis.
Hypermethylation in the promoter region of BLU was detected in 34 of 79 (43%) newly diagnosed MDS patient samples and was significantly correlated with the loss of BLU mRNA and protein expression. There was a statistically significant difference in methylation frequency between the refractory anemia/refractory anemia with ringed sideroblasts/5q-syndrome (RA/RARS/5q-) group and the refractory anemia with excess blasts-1/-2 (RAEB-1/RAEB-2) group. A higher frequency of hypermethylation was observed in the intermediate-2/high-risk group compared to the low-risk/intermediate-1-risk group. The demethylating agent decitabine could partly reverse hypermethylation and restore the expression of the BLU gene.
BLU promoter hypermethylation frequently occurs in MDS cases, especially in higher risk MDS cases, and is significantly associated with the downregulated expression of BLU. BLU gene re-expression was induced in some MDS cases undergoing decitabine therapy. BLU may play a substantial role in the development and etiology of MDS.
Journal of Cancer Research and Clinical Oncology 01/2012; 138(5):729-37. · 2.56 Impact Factor
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ABSTRACT: The polycomb group (PcG) protein BMI1 plays a critical role in regulating self renewal capacity of both normal and leukemic stem cells. BMI1 is frequently overexpressed in several types of cancer, which is associated with poor prognosis. However, there are few researches on BMI1 in myelodysplastic syndromes (MDS). In this study, we reported that overexpression of BMI1 protein was detected in MDS patients, and inversely correlated with the apoptosis of CD34+ cells. In vitro overexpression of BMI1 facilitated proliferation and inhibited apoptosis of MDS-L cells. The overexpression of BMI1 could downregulate apoptosis sensitivity to cytotoxic agents in MDS-L cells; on the contrary, MDS-L cells could be rendered apoptosis-sensitive by BMI1 knockdown. Overexpression of BMI1 antagonised apoptosis by downregulating several apoptosis-related proteins, such as p16(INK4a), phospho-p53 (Ser46) and caspase 3/9. In addition, overexpression of BMI1 was correlated with an elevated IPSS score and a shorter survival. Collectively, overexpression of BMI1 induces resistance to apoptosis and contributes to adverse prognosis in MDS. BMI1 could serve as a therapeutic target for patients with MDS.
Cancer letters 11/2011; 317(1):33-40. · 4.86 Impact Factor
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ABSTRACT: Epigenetics refers to the study of clonally inherited changes in gene expression without accompanying genetic changes. Previous research on the epigenetics of myelodysplastic syndromes (MDS) mainly focused on the inactivation of tumor suppressor genes as a result of DNA methylation. However, the basic molecular pathogenesis of epigenetics in MDS remains poorly understood. Recent studies have revealed that DNA methylation and histone modification may be controlled by Polycomb-group (PcG) proteins, which may give new clues toward understanding the epigenetic mechanism of MDS. In this study, we explored for the first time the expression of PcG genes, including EZH2, EED, SUZ12, RING1, and BMI1, in various MDS subsets and acute myeloid leukemia (AML), as well as the relationship between the expression of PcG genes and epigenetic alteration and prognosis-risk scoring. Patients with MDS/AML showed overexpression of EZH2, RING1, and BMI1 genes compared to their expression levels in patients with non-clonal cytopenia diseases. The MDS patients with DNA methylation had higher EZH2 expression than those without DNA methylation. The patients who received decitabine treatment presented significantly reduced expression of EZH2 and RING1 besides decreased p15(INK4B) methylation after decitabine treatment. Moreover, overexpression of EZH2, RING1, and BMI1 was always linked to poor prognostic scoring. In conclusion, overexpression of the EZH2, RING1, and BMI1 genes is common in MDS and indicate poor prognosis. The products of these genes might participate in epigenetic regulation of MDS. These studies may also contribute to our understanding of the effective mechanism of decitabine.
Annals of Hematology 12/2010; 90(6):643-53. · 2.62 Impact Factor
