DNA methylation markers in the diagnosis and prognosis of common leukemias

Jiang, Hua; Ou, Zhiying; He, Yingyi; Yu, Mei; Wu, Shaohua; Li, Gen; Zhu, Jie; Zhang, Ru; Wang, Jiayi; Zheng, Lianghong; Zhang, Xiaohong; Hao, Wen-Ge; He, Liang; Gu, Xiaoqiong; Quan, Qingli; Zhang, Edward; Luo, Hongyu; Wei, Wei; Li, Zhihuan; Zang, Guangxi; Zhang, Charlotte; Poon, Tina; Zhang, Dongke; Ziyar, Ian; Zhang, Run-Ze; Li, Oulan; Cheng, Linhai; T, Shimizu; Cui, Xinping; Zhu, Jian‐Kang; Sun, Xin; Zhang, Kang

doi:10.1038/s41392-019-0090-5

Cited by 27 publications

(19 citation statements)

References 41 publications

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“…Emerging studies have already shed light on a role for epigenetic dysregulation and classification in both ALL and AML. For example, methylation profiling of CpG sites can predict survival in each subtype [ 49 ], as well as can be used to distinguish lymphoid from myeloid cases [ 49 , 50 ]. We report here that, besides CpG methylation, global histone modification is also differentially expressed between lymphoid and myeloid leukemia and measurement at time of diagnosis correlates with response to therapy.…”

Section: Discussionmentioning

confidence: 99%

Loss of H3K27 methylation identifies poor outcomes in adult-onset acute leukemia

et al. 2021

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Background Acute leukemia is an epigenetically heterogeneous disease. The intensity of treatment is currently guided by cytogenetic and molecular genetic risk classifications; however these incompletely predict outcomes, requiring additional information for more accurate outcome predictions. We aimed to identify potential prognostic implications of epigenetic modification of histone proteins, with a focus on H3K4 and H3K27 methylation marks in relation to mutations in chromatin, splicing and transcriptional regulators in adult-onset acute lymphoblastic and myeloid leukemia. Results Histone 3 lysine 4 di- and trimethylation (H3K4me2, H3K4me3) and lysine 27 trimethylation (H3K27me3) mark expression was evaluated in 241 acute myeloid leukemia (AML), 114 B-cell acute lymphoblastic leukemia (B-ALL) and 14T-cell ALL (T-ALL) patient samples at time of diagnosis using reverse phase protein array. Expression levels of the marks were significantly lower in AML than in B and T-ALL in both bone marrow and peripheral blood, as well as compared to normal CD34+ cells. In AML, greater loss of H3K27me3 was associated with increased proliferative potential and shorter overall survival in the whole patient population, as well as in subsets with DNA methylation mutations. To study the prognostic impact of H3K27me3 in the context of cytogenetic aberrations and mutations, multivariate analysis was performed and identified lower H3K27me3 level as an independent unfavorable prognostic factor in all, as well as in TP53 mutated patients. AML with decreased H3K27me3 demonstrated an upregulated anti-apoptotic phenotype. In ALL, the relative quantity of histone methylation expression correlated with response to tyrosine kinase inhibitor in patients who carried the Philadelphia cytogenetic aberration and prior smoking behavior. Conclusion This study shows that proteomic profiling of epigenetic modifications has clinical implications in acute leukemia and supports the idea that epigenetic patterns contribute to a more accurate picture of the leukemic state that complements cytogenetic and molecular genetic subgrouping. A combination of these variables may offer more accurate outcome prediction and we suggest that histone methylation mark measurement at time of diagnosis might be a suitable method to improve patient outcome prediction and subsequent treatment intensity stratification in selected subgroups.

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Section: Discussionmentioning

confidence: 99%

Loss of H3K27 methylation identifies poor outcomes in adult-onset acute leukemia

et al. 2021

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“…Both in vitro and in vivo assays revealed that HIST2H2BF promotes malignant tumor behaviors in CRC. DNA methylation deregulation contributes markedly to tumor progression and acts as a vital marker to predict the response to therapy and prognosis in tumors (27,28). In our study, we examined the methylation levels of the HIST2H2BF promoter with methylation-specific PCR and bisulfite sequencing PCR in CRC tissues and adjacent normal tissues.…”

Section: Discussionmentioning

confidence: 99%

HIST2H2BF Potentiates the Propagation of Cancer Stem Cells via Notch Signaling to Promote Malignancy and Liver Metastasis in Colorectal Carcinoma

Qiu

Yang

et al. 2021

Front. Oncol.

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BackgroundGrowing evidence demonstrates that the initiation and progression of colorectal carcinoma (CRC) is related to the presence of cancer stem cells (CSCs). However, the mechanism through which the stem cell features of CRC cells are maintained is poorly understood. In this study, we identified the oncogenic histone cluster 2 H2B family member F (HIST2H2BF) and aimed to investigate the function of upregulated HIST2H2BF expression in maintaining the stem cell features of CRC cells, which accelerate the progression of CRC.MethodsHIST2H2BF expression was quantified using real-time polymerase chain reaction, immunohistochemistry, and western blotting. The correlation between CpG island methylation status and HIST2H2BF re-expression was assessed through bisulfite sequencing polymerase chain reaction, methylation-specific polymerase chain reaction, and 5-Aza-dC treatment. Functional assays were performed on CRC cells and mice to investigate the HIST2H2BF-induced stem cell-like and cancer properties of CRC. Using the Notch pathway inhibitor FLI-06, the regulatory effect of HIST2H2BF on downstream Notch signaling was confirmed.ResultsHIST2H2BF was highly expressed in CRC tissues and cell lines. The reactivation of HIST2H2BF in CRC stems at least in part from the hypomethylated CpG islands. CRC patients with high HIST2H2BF expression have poor survival outcomes. Functional studies have shown that HIST2H2BF promotes CSC phenotype, malignancy, and liver metastasis through the activation of Notch signaling in CRC. Blockage of the Notch pathway reduced the stem cell-like and cancer properties.ConclusionOur study suggests that HIST2H2BF upregulation enhances the CSC phenotype, malignancy, and liver metastasis through the activation of Notch signaling in CRC. These results identified a new perspective on the mechanism by which the stem cell features of CRC cells are maintained and highlighted the potential novel therapeutic targets for CRC.

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“…Recent researches have demonstrated epigenetic modifications act a critical role in AML through altering the transcriptional activation of oncogenes or tumor suppressors (6)(7)(8). DNA methylation is a common epigenetic modification in biological process and pathological processes in multiple tumors, such as regulation of tumorigenesis and development in breast cancer and lung cancer (9,10). Previous study has found that there is abnormal DNA methylation before cancer cell mutation (11).…”

Section: Introductionmentioning

confidence: 99%

“…Inhibiting the expression of DNA methylation can effectively improve the effect of chemotherapy and prolong the survival time of AML patients ( 22 ). Previous studies have found that DNA methylation is a high sensitivity and specificity biomarker of AML in distinguishing it from other leukemia ( 9 ). Besides DNA methylation being strongly associated with prognosis of AML patients, it has been reported that different methylation types have different clinical outcomes for AML patients ( 23 ).…”

Section: Introductionmentioning

confidence: 99%

Integrative Analysis of Multi-Omics Identified the Prognostic Biomarkers in Acute Myelogenous Leukemia

et al. 2020

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BackgroundAcute myelogenous leukemia (AML) is a common pediatric malignancy in children younger than 15 years old. Although the overall survival (OS) has been improved in recent years, the mechanisms of AML remain largely unknown. Hence, the purpose of this study is to explore the differentially methylated genes and to investigate the underlying mechanism in AML initiation and progression based on the bioinformatic analysis.MethodsMethylation array data and gene expression data were obtained from TARGET Data Matrix. The consensus clustering analysis was performed using ConsensusClusterPlus R package. The global DNA methylation was analyzed using methylationArrayAnalysis R package and differentially methylated genes (DMGs), and differentially expressed genes (DEGs) were identified using Limma R package. Besides, the biological function was analyzed using clusterProfiler R package. The correlation between DMGs and DEGs was determined using psych R package. Moreover, the correlation between DMGs and AML was assessed using varElect online tool. And the overall survival and progression-free survival were analyzed using survival R package.ResultsAll AML samples in this study were divided into three clusters at k = 3. Based on consensus clustering, we identified 1,146 CpGs, including 40 hypermethylated and 1,106 hypomethylated CpGs in AML. Besides, a total 529 DEGs were identified, including 270 upregulated and 259 downregulated DEGs in AML. The function analysis showed that DEGs significantly enriched in AML related biological process. Moreover, the correlation between DMGs and DEGs indicated that seven DMGs directly interacted with AML. CD34, HOXA7, and CD96 showed the strongest correlation with AML. Further, we explored three CpG sites cg03583857, cg26511321, cg04039397 of CD34, HOXA7, and CD96 which acted as the clinical prognostic biomarkers.ConclusionOur study identified three novel methylated genes in AML and also explored the mechanism of methylated genes in AML. Our finding may provide novel potential prognostic markers for AML.

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DNA methylation markers in the diagnosis and prognosis of common leukemias

Cited by 27 publications

References 41 publications

Loss of H3K27 methylation identifies poor outcomes in adult-onset acute leukemia

Loss of H3K27 methylation identifies poor outcomes in adult-onset acute leukemia

HIST2H2BF Potentiates the Propagation of Cancer Stem Cells via Notch Signaling to Promote Malignancy and Liver Metastasis in Colorectal Carcinoma

Integrative Analysis of Multi-Omics Identified the Prognostic Biomarkers in Acute Myelogenous Leukemia

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