Abstract
BackgroundMyelodysplastic syndrome (MDS) can progress to acute myeloid leukemia (AML), and conventional chemotherapy (decitabine) does not effectively inhibit tumor cells. Enhancer of zeste homologue 2 (EZH2) and Heme oxygenase-1 (HO-1) are two key factors in patients resistance and deterioration.MethodsIn total, 58 MDS patients were divided into four groups. We analyzed the difference in HO-1 and EZH2 expression among the groups by real-time PCR. After treatment with Hemin or Znpp IX, flow cytometry was used to detect apoptosis and assess the cell cycle distribution of tumor cells. Following injection of mice with very high-risk MDS cells, spleen and bone marrow samples were studied by immunohistochemistry (IHC) and hematoxylin and eosin (H&E) staining. MDS cells overexpressing EZH2 and HO-1 were analyzed by high-throughput sequencing. The effect of HO-1 on the pRB-E2F pathway was analyzed by Western blotting. The effects of decitabine on P15INK4B and TP53 in MDS cells after inhibiting HO-1 were detected by Western blotting.ResultsReal-time PCR results showed that EZH2 and HO-1 expression levels were higher in MDS patients than in normal donors. The levels of HO-1 and EZH2 were simultaneously increased in the high-risk and very high-risk groups. Linear correlation analysis and laser scanning confocal microscopy results indicated that EZH2 was related to HO-1. MDS cells that highly expressed EZH2 and HO-1 infiltrated the tissues of experimental mice. IHC results indicated that these phenomena were related to the pRB-E2F pathway. High-throughput sequencing indicated that the progression of MDS to AML was related to EZH2. Using the E2F inhibitor HLM006474 and the EZH2 inhibitor JQEZ5, we showed that HO-1 could regulate EZH2 expression. HO-1 could stimulate the transcription and activation of EZH2 through the pRB-E2F pathway in MDS patients during chemotherapy, which reduced TP53 and P15INK4B expression.ConclusionsEZH2 was associated with HO-1 in high-risk and very high-risk MDS patients. HO-1 could influence MDS resistance and progression to AML.
Highlights
Myelodysplastic syndrome (MDS) can progress to acute myeloid leukemia (AML), and conventional chemotherapy does not effectively inhibit tumor cells
Enhancer of zeste homologue 2 (EZH2) and HO‐1 are relevant in some high‐risk and very high‐risk MDS patients According to the World Health Organization (WHO) prognostic scoring system (WPSS), we divided 58 MDS patients into four different groups
Heme oxygenase-1 (HO-1) and EZH2 expression levels were simultaneously increased in some patients, especially those in the high-risk and very high-risk groups (Fig. 1a)
Summary
Myelodysplastic syndrome (MDS) can progress to acute myeloid leukemia (AML), and conventional chemotherapy (decitabine) does not effectively inhibit tumor cells. A study indicated that combining inhibition of EZH2 and LSD1 resulted in synergistic activity against AML in vitro and in vivo. This synergy was mechanistically correlated with upregulation of H3K4me1/2 and H3K9Ac and downregulation of H3K27me, leading to a decrease in the level of the antiapoptotic protein Bcl-2 [8]. Other studies have shown that EZH2 can increase cancer cell aggressiveness [9,10,11] It is not known whether MDS patients can progress to AML following EZH2 overexpression. It is unclear whether EZH2 inhibition has inhibitory effects on high-risk or very high-risk MDS progression
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