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  • Wiley  (13)
  • Lin, Jiang  (13)
  • 1
    In: Journal of Cellular and Molecular Medicine, Wiley, Vol. 23, No. 5 ( 2019-05), p. 3317-3324
    Abstract: The clinical activity of decitabine (5‐aza‐2‐deoxycytidine, DAC), a hypomethylating agent, has been demonstrated in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients. However, secondary resistance to this agent often occurs during treatment and leads to treatment failure. It is important to clarify the mechanisms underlying the resistance for improving the efficacy. In this study, by gradually increasing concentration after a continuous induction of DAC, we established the DAC‐resistant K562 cell line (K562/DAC) from its parental cell line K562. The proliferation and survival rate of K562/DAC was significantly increased, whereas the apoptosis rate was remarkably decreased than that of K562 after DAC treatment. In K562/DAC, a total of 108 genes were upregulated and 118 genes were downregulated by RNA‐Seq. In addition, we also observed aberrant expression of DDX43/H19/miR‐186 axis (increased DDX43 / H19 and decreased miR‐186 ) in K562/DAC cells. Ectopic expression of DDX43 in parental K562 cells rendered cells resistant to the DAC. Taken together, we successfully established DAC‐resistant K562 cell line which can serve as a good model for investigating DAC resistance mechanisms, and DDX43/H19/miR‐186 may be involved in DAC resistance in K562.
    Type of Medium: Online Resource
    ISSN: 1582-1838 , 1582-4934
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2076114-4
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  • 2
    In: Molecular Genetics & Genomic Medicine, Wiley, Vol. 8, No. 1 ( 2020-01)
    Abstract: Previous studies have disclosed up‐regulation of MIR‐378 in acute myeloid leukemia (AML), and might consequently affect the outcome of the patients. Correspondingly, hypomethylation of MIR‐378 was also identified in AML, particularly for FAB‐M2 subtype with t(8;21) chromosomal translocation. Nevertheless, the methylation status of MIR‐378 has not been illustrated in myelodysplastic syndrome (MDS). Herein we designed to understand the methylation pattern of MIR‐378 involved in MDS and clinical interrelation thereof. Methods Real‐time quantitative methylation‐specific PCR (RQ‐MSP) was performed to evaluate the methylation degree of MIR‐378 5’‐flanking region on bone marrow mononuclear cells collected from 95 de novo MDS patients. Five gene mutations ( IDH1 , IDH2 , DNMT3A , U2AF1 , and SF3B1 ) were detected by high‐resolution melting analysis to further evaluate the clinical relevance of hypomethylation of MIR‐378 . Results Unmethylated level of MIR‐378 5’‐flanking region was significantly higher in MDS patients than that in controls ( p  = .034). Hypomethylated MIR‐378 was identified in 20 of 95 (21%) cases with MDS. Male patients appeared to be more frequent to harbor MIR‐378 hypomethylation compared to female patients (15/55, 27.3% vs. 4/40, 10.0%, p =  .04). There was no significant difference in age, white blood cell counts, platelet counts, hemoglobin concentration, and karyotypes between the patients with and without MIR‐378 ‐hypomethylation. Distinct distribution of five gene mutations was not observed in the two groups as well. However, MIR‐378 ‐hypomethylated patients had significantly shorter overall survival than those without MIR‐378 hypomethylation ( p =  .036). Moreover, among patients 〈 60 years, hypomethylation of MIR‐378 was confirmed to be an independent adverse prognostic factor by both Kaplan–Meier and Multivariate Cox analyses. Conclusion Hypomethylation of MIR‐378 5’‐flanking region is an adverse prognosticator in MDS, particularly in patients 〈 60 years.
    Type of Medium: Online Resource
    ISSN: 2324-9269 , 2324-9269
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2734884-2
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  • 3
    In: Journal of Cellular and Molecular Medicine, Wiley, Vol. 24, No. 2 ( 2020-01), p. 1640-1649
    Abstract: Accumulating studies have proved EZH2 dysregulation mediated by mutation and expression in diverse human cancers including AML. However, the expression pattern of EZH2 remains controversial in acute myeloid leukaemia (AML). EZH1/2 expression and mutation were analysed in 200 patients with AML. EZH2 expression was significantly decreased in AML patients compared with normal controls but not for EZH1 expression. EZH2 mutation was identified three of the 200 AML patients (1.5%, 3/200), whereas none of the patients harboured EZH1 mutation (0%, 0/200). EZH2 expression and mutation were significantly associated with −7/del(7) karyotypes. Moreover, lower EZH2 expression was associated with older age, higher white blood cells, NPM1 mutation, CEBPA wild‐type and WT1 wild‐type. Patients with EZH2 mutation showed shorter overall survival (OS) and leukaemia‐free survival (LFS) than patients without EHZ2 mutation after receiving autologous or allogeneic haematopoietic stem cell transplantation (HSCT). However, EZH2 expression has no effect on OS and LFS of AML patients. Notably, in EZH2 low group, patients undergone HSCT had significantly better OS and LFS compared with patients only received chemotherapy, whereas no significant difference was found in OS and LFS between chemotherapy and HSCT patients in EZH2 high group. Collectively, EZH2 dysregulation caused by mutation and under‐expression identifies specific subtypes of AML EZH2 dysregulation may be acted as potential biomarkers predicting prognosis and guiding the treatment choice between transplantation and chemotherapy.
    Type of Medium: Online Resource
    ISSN: 1582-1838 , 1582-4934
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2076114-4
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  • 4
    In: Clinical and Translational Medicine, Wiley, Vol. 10, No. 2 ( 2020-06)
    Abstract: The deregulated DLX gene family members DLX1/2/3/4/5/6 ( DLXs ) caused by DNA methylation has been demonstrated in various cancers with therapeutic target value. However, the potential role of DLXs methylation in myeloid neoplasms such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) remains to be elucidated. Clinical significance of DLXs methylation/expression was analyzed in patient with AML and MDS. The functional roles of DLXs were determined in vitro. In the identification stage, we found that lower DLX5 expression was correlated with prognosis in AML among all DLXs analyzed by The Cancer Genome Atlas datasets. In the validation stage, we revealed that reduced DLX5 expression was frequently occurred, and was also correlated with promoter hypermethylation in AML evaluated by targeted bisulfite sequencing. Epigenetic studies also showed that DLX5 promoter DNA methylation was associated with its expression. By quantitative polymerase chain reaction, we also validated that DLX5 hypermethylation was frequent event in both AML and MDS, and also correlated with MDS transformation to leukemia. Moreover, DLX5 hypermethylation was associated with lower rate of complete remission and shorter time of leukemia‐free/overall survival, and was also confirmed by Logistic/Cox regression analysis. Functional studies revealed the antiproliferative and pro‐apoptotic effects of DLX5 in MDS‐derived AML cell‐line SKM‐1. Finally, bioinformatics analysis demonstrated that DLX5 functioned in leukemogenesis may be through the association with PI3K/Akt signaling pathway. Collectively, our findings demonstrated that DLX5 methylation, negatively correlated DLX5 expression, was a potential prognostic and predictive indicator in patients with AML and MDS, which could also act as an epigenetic driver in myeloid neoplasms.
    Type of Medium: Online Resource
    ISSN: 2001-1326 , 2001-1326
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2697013-2
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  • 5
    In: Cancer Medicine, Wiley, Vol. 12, No. 1 ( 2023-01), p. 789-807
    Abstract: CD300s are a group of proteins playing vital roles in immune responses. However, much is yet to be elucidated regarding the expression patterns and clinical significances of CD300s in cancers. Methods In this study, we comprehensively investigated CD300s in a pan‐cancer manner using multi‐omic data from The Cancer Genome Atlas. We also studied the relationship between CD300s and the immune landscape of AML. Results We found that CD300A ‐ CD300LF were generally overexpressed in tumors (especially AML), whereas CD300LG was more often downregulated. In AML, transactivation of CD300A was not mediated by genetic alterations but by histone modification. Survival analyses revealed that high CD300A ‐ CD300LF expression predicted poor outcome in AML patients; the prognostic value of CD300A was validated in seven independent datasets and a meta dataset including 1115 AML patients. Furthermore, we demonstrated that CD300A expression could add prognostic value in refining existing risk models in AML. Importantly, CD300A ‐ CD300LF expression was closely associated with T‐cell dysfunction score and could predict response to AML immunotherapy. Also, CD300A was found to be positively associated with HLA genes and critical immune checkpoints in AML, such as VISTA , CD86 , CD200R1 , Tim‐3 , and the LILRB family genes. Conclusions Our study demonstrated CD300s as potential prognostic biomarker and an ideal immunotherapy target in AML, which warrants future functional and clinical studies.
    Type of Medium: Online Resource
    ISSN: 2045-7634 , 2045-7634
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2659751-2
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  • 6
    In: Journal of Cellular Physiology, Wiley, Vol. 233, No. 3 ( 2018-03), p. 2444-2450
    Abstract: Previous study has revealed that H19 expression is required for efficient tumor growth induced by BCR‐ABL in chronic myeloid leukemia (CML). Herein, we further determined H19 expression and its clinical implication in patients with CML. H19 expression and methylation were detected by real‐time quantitative PCR and real‐time quantitative methylation‐specific PCR, and then clinical implication of H19 expression was further analyzed. H19 expression was significantly up‐regulated in CML patients ( p  〈  0.001). H19 expression with an area under receiver operating characteristic curve value of 0.824 might serve as a promising biomarker in distinguishing CML patients from controls. The patients with high H19 expression had a tendency of higher white blood cells and BCR‐ABL transcript than those with low H19 expression. H19 overexpression occurred with the higher frequency in blast crisis stage (11/11, 100%), lower in accelerated phase (3/5, 60%), and chronic phase (42/62, 66%) stages. Moreover, paired patients during disease progression with increased BCR‐ABL transcript also showed a significant upregulation of H19 expression. Meanwhile, H19 expression was decreased in follow‐up patients who achieved complete molecular remission after tyrosine kinase inhibitors‐based therapy. Epigenetic studies showed that H19 differentially methylated region/imprinting control region (DMR/ICR) was hypomethylated and associated with H19 expression in CML patients. Moreover, demethylation of H19 DMR/ICR reactivated H19 expression in K562 cells. Collectively, H19 overexpression, a frequent event in CML, was associated with higher BCR‐ABL transcript involving in disease progression. Moreover, H19 DMR/ICR hypomethylation in CML may be one of the mechanisms mediating H19 overexpression.
    Type of Medium: Online Resource
    ISSN: 0021-9541 , 1097-4652
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 1478143-8
    SSG: 12
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  • 7
    In: Journal of Cellular Physiology, Wiley, Vol. 233, No. 12 ( 2018-12), p. 9584-9593
    Abstract: Previous studies have been indicated that integrin α2 (ITGA2) may be important in cell migration, invasion, survival, and angiogenesis. However, the correlation between ITGA2 expression and acute myeloid leukemia (AML) is still unclear. Real‐time quantitative polymerase chain reaction was carried out to analyze ITGA2 messenger RNA level. Methylation‐specific polymerase chain reaction (PCR) and bisulfite sequencing PCR were performed to detect the methylation of ITGA2 promoter. ITGA2 expression was significantly upregulated in 134 de novo AML patients compared with 33 controls ( p  = 0.007). ITGA2 high group had markedly lower complete remission (CR) rate than ITGA2 low group ( p  = 0.011). Furthermore, the overall survival in ITGA2 high patients was significantly shorter than ITGA2 low patients throughout AML cohort, non–acute promyelocytic leukemia (APL) and cytogenetic normal‐AML ( p  = 0.001, 0.002, and 0.044, respectively). Multivariate analysis confirmed that ITGA2 overexpression served as an independent prognostic factor in both whole‐cohort AML patients ( p  = 0.018) and non‐APL AML patients ( p  = 0.021). Besides, ITGA2 expression level was significantly decreased in AML patients after CR ( p  = 0.011), and was returned at the time of relapse phase ( p  = 0.021). Moreover, unmethylated ITGA2 promoter was identified in normal controls, leukemia cell lines, and primary leukemia cells with low or high ITGA2 expression. In conclusions, methylation‐independent ITGA2 overexpression is associated with poor prognosis in AML.
    Type of Medium: Online Resource
    ISSN: 0021-9541 , 1097-4652
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 1478143-8
    SSG: 12
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  • 8
    In: Molecular Carcinogenesis, Wiley, Vol. 57, No. 6 ( 2018-06), p. 735-744
    Abstract: The present study was aimed to investigate SCIN expression as well as promoter methylation and further explore their clinical relevance in acute myeloid leukemia (AML) patients. Real‐time quantitative PCR was carried out to detect the expression level of SCIN in 119 AML patients and 37 healthy controls. Real‐time quantitative methylation‐specific PCR and bisulfite sequencing PCR were carried out to detect SCIN promoter methylation levels in 103 AML patients and 29 controls. As compared with controls, the level of SCIN transcript was significantly down‐regulated in AML patients ( P  = 0.001), and the level of methylated SCIN promoter was significantly higher in AML patients ( P  = 0.001). Moreover, the level of promoter methylation was weakly negatively correlated with SCIN expression in AML patients ( R  = −0.265, P  = 0.027). Demethylation of SCIN promoter by 5‐aza‐2′‐deoxycytidine could restore its expression in leukemic cell line THP1. The age of SCIN low patients was significantly higher and C/EBPA mutation was significantly less than SCIN high patients ( P  = 0.039 and 0.038, respectively). Moreover, the rate of complete remission (CR) of SCIN low patients was significantly lower than SCIN high patients ( P  = 0.009). Kaplan‐Meier analysis showed that low SCIN expression was associated with shorter overall survival ( P  = 0.036). Cox regression analysis demonstrated low SCIN expression was an independent poor prognostic factor ( P  = 0.047). Furthermore, SCIN expression was restored in those patients who achieved CR after induction therapy ( P  = 0.003). These findings indicate that decreased SCIN expression associated with its promoter methylation is a valuable biomarker for predicting adverse prognosis in AML patients.
    Type of Medium: Online Resource
    ISSN: 0899-1987 , 1098-2744
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2001984-1
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  • 9
    Online Resource
    Online Resource
    Wiley ; 2009
    In:  European Journal of Haematology Vol. 82, No. 2 ( 2009-02), p. 119-123
    In: European Journal of Haematology, Wiley, Vol. 82, No. 2 ( 2009-02), p. 119-123
    Abstract: The death‐associated protein kinase 1 ( DAPK1 ) gene is a candidate tumor suppressor (TSG) and the abnormal methylation of DAPK1 gene has been found in many carcinomas. The epigenetic changes of TSGs are now recognized as a mechanism contributing to the development of chronic myeloid leukemia (CML). To clarify the role of DAPK1 in CML, we examined the methylation status of DAPK1 in 49 patients with CML using methylation‐specific polymerase chain reaction. The aberrant methylation of the DAPK1 gene was found in 25 of 49 (51.0%) CML cases, not in all controls. No correlation was found between DAPK1 gene methylation and the age, hematologic parameters, chromosomal abnormalities, the types and levels of bcr/abl transcripts of CML patients. However, correlation could be observed between the sex and the status of DAPK1 methylation in CML patients ( R  = 0.374, P  =   0.008). Furthermore, there was a significant correlation between DAPK1 methylation and the stages of CML ( R  = 0.354, P  =   0.013). The CML patients in accelerated phase (AP) and blast crisis (BC) had higher frequency of DAPK1 methylation than those in chronic phase (CP) (75.0% vs. 34.5%) (χ 2  = 7.776, P  =   0.005). In one patient, the status of DAPK1 methylation became positive on the transition from CP to AP and BC. These results suggested that DAPK1 promoter methylation might play a significant role in the progression of CML.
    Type of Medium: Online Resource
    ISSN: 0902-4441 , 1600-0609
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2009
    detail.hit.zdb_id: 2027114-1
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  • 10
    In: Journal of Cellular Physiology, Wiley, Vol. 233, No. 8 ( 2018-08), p. 5838-5846
    Abstract: TET2 (Ten‐Eleven Translocation 2) gene is a member of TET family that can modify DNA through catalyzing the conversion of 5‐methylcytosine (5‐mC) into 5‐hydroxymethylcytosine (5‐hmC). Although TET2 mutation has been disclosed in a variety of hematopoietic malignancies, the prognostic implication of TET2 expression in acute myeloid leukemia (AML) remains largely elusive. In this study, real‐time quantitative PCR was carried out to detect the level of TET2 transcript in 134 de novo AML patients and 35 healthy donors. TET2 mRNA level was significantly down‐regulated in AML patients compared with controls ( p  = 0.010). Among the French–American–British (FAB) subtypes, the incidence of TET2 under‐expression in M0/M1 subtypes was significantly higher than in the other subtypes M2/M3/M4/M5/M6 ( p  = 0.017), and also markedly higher than in the other granulocyte subtypes M2/M3 ( p  = 0.005). TET2 low‐expressed patients showed a significantly higher frequency of NPM1 mutations than TET2 high‐expressed patients. Although there was no significant difference in complete remission rate between two groups (low and high TET2 expression), patients with low TET2 expression had markedly shorter overall survival (OS) in both non‐M3 and cytogenetically normal AML (CN‐AML) ( p  = 0.016 and 0.044, respectively). Furthermore, multivariate analysis confirmed the prognostic value of TET2 expression on OS among CN‐AML patients ( p  = 0.049). Importantly, TET2 expression in complete remission (CR) time was significantly higher than newly diagnosis time ( p  = 0.001), and was returned to lower level when in relapse time ( p  〈  0.001). These findings indicated that down‐regulation of TET2 expression was a common event and acted as a prognostic and predictive biomarker in CN‐AML patients.
    Type of Medium: Online Resource
    ISSN: 0021-9541 , 1097-4652
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 1478143-8
    SSG: 12
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