Decreased <i>SCIN</i> expression, associated with promoter methylation, is a valuable predictor for prognosis in acute myeloid leukemia

Zhang, Zhihui; Zhang, Wei; Zhou, Jing‐Dong; Zhang, Ting‐Juan; Ma, Ji‐chun; Xu, Zi‐jun; Lian, Xin‐Yue; Wu, Dehong; Wen, Xiang‐mei; Deng, Zhaoqun; Jiang, Lin; Qian, Jun

doi:10.1002/mc.22794

Cited by 15 publications

(12 citation statements)

References 32 publications

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“…1F). Notably, low SCIN expression is associated with an adverse AML prognosis 34 . Two other genes of interest for which expression also correlates with a DHS at nearby ERVs are TPD52 and AHSP, whose overexpression in AML is predictive of poor and favourable outcomes, respectively 35,36 .…”

Section: Resultsmentioning

confidence: 99%

Endogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia

et al. 2020

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Acute myeloid leukemia (AML) is characterised by a series of genetic and epigenetic alterations that result in deregulation of transcriptional networks. One understudied source of transcriptional regulators are transposable elements (TEs), whose aberrant usage could contribute to oncogenic transcriptional circuits. However, the regulatory influence of TEs and their links to AML pathogenesis remain unexplored. Here we identify six endogenous retrovirus (ERV) families with AML-associated enhancer chromatin signatures that are enriched in binding of key regulators of hematopoiesis and AML pathogenesis. Using both locus-specific genetic editing and simultaneous epigenetic silencing of multiple ERVs, we demonstrate that ERV deregulation directly alters the expression of adjacent genes in AML. Strikingly, deletion or epigenetic silencing of an ERV-derived enhancer suppresses cell growth by inducing apoptosis in leukemia cell lines. This work reveals that ERVs are a previously unappreciated source of AML enhancers that may be exploited by cancer cells to help drive tumour heterogeneity and evolution.

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Section: Resultsmentioning

confidence: 99%

Endogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia

et al. 2020

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“…Nonetheless, we found ERVs with strong supporting evidence for their regulatory activity, as the expression levels of their vicinity genes were >4-fold higher in AML samples with DHS at a given ERV, versus those without ( Figure 1E). This included a strict correlation between chromatin accessibility at a LTR12C element and the expression of the SCIN gene ( Figure 1F), which has a mild predictive value for AML prognosis (Z.-H. Zhang et al, 2018). TPD52 and AHSP expression, which were correlated with the presence of DHS at a LTR12C and LTR5B element respectively, have also been linked to AML prognosis (Ha et al, 2019;Zhu et al, 2017).…”

Section: A-dar Chromatin Status Correlates With Nearby Gene Expressionmentioning

confidence: 96%

Endogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia

Deniz

Ahmed

Todd

et al. 2019

Preprint

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Endogenous retroviruses (ERVs) and other transposons can act as tissue-specific regulators of gene expression in cis, with potential to affect biological processes. In cancer, epigenetic alterations and transcription factor misregulation may uncover the regulatory potential of typically repressed ERVs, which could contribute to tumour evolution and progression. Here, we asked whether transposons help to rewire oncogenic transcriptional circuits in acute myeloid leukemia (AML). Using epigenomic data from both primary cells and cell lines, we have identified six ERV families that are frequently found in an open chromatin state in AML when compared to differentiated healthy myeloid cells. A subset of these AML-associated ERVs harbour enhancerspecific histone modifications, and are bound by hematopoiesis-associated transcription factors that play key roles in haematopoiesis and in the pathogenesis of AML. Using CRISPR-mediated genetic editing and simultaneous epigenetic silencing of multiple ERV copies, we have established causal links between ERV deregulation in AML and expression changes of adjacent genes. Finally, we show that deletion and epigenetic silencing of an ERV, through modulating expression of APOC1 gene, leads to growth suppression by inducing apoptosis in leukemia cell lines. Our results suggest that ERV derepression provides an additional layer of gene regulation in AML that may be exploited by cancer cells to help drive oncogenic phenotypes. 10% or more of the AML samples ( Figure 1B). Five of these families were highly enriched across all samples, including macrophages and monocytes, as well as mobilized CD34+ cells (data from the Roadmap epigenomics project), suggesting little cell specificity. The remaining seven families displayed more variability between AML samples and, notably, tended to display little to no enrichment in differentiated myeloid cells ( Figure 1B). Nearly all families were also DHS-enriched in CD34+ cells, suggesting an association with a stem cell state. The exception was the LTR2B family, whose DHS enrichment appeared to be AML-specific. Analysis of an independent

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“…In this study, we finalized the relevant gene "KRT23 ULBP2 ASRGL1 SERPINA1 SCIN SLC28A2" that may affect Th-17 cells immune infiltration in COAD patients. We have now found that these genes are involved in the development of many diseases (42)(43)(44)(45)(46)(47)(48)(49),In non-gastrointestinal tumors, ASRGL1 has shown a high correlation in the prognosis of patients with locally advanced lymph node-negative prostate cancer and cervical cancer (42,50); SLC28A2 helps increase the role of ribavirin (RBV) in the treatment of viral hepatitis Hyperuricemia (HUA) has been implicated (48,51). KRT23 was identified as a specifically expressed gene in colorectal cancer and highly expressed in colorectal cancer (45).…”

Section: Discussionmentioning

confidence: 99%

Screening of immunosuppressive cells from colorectal adenocarcinoma and identification of prognostic markers

Zhou

et al. 2020

Preprint

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Background Colorectal cancer (CRC) is the most common type of gastrointestinal malignant tumor. Colorectal adenocarcinoma (COAD) is the most common type of colorectal cancer, and it is extremely harmful to human life and health. In recent years, the role of the immune system in the development of tumor-associated inflammation and cancer has received increasing attention. Results In this study, we compiled the expression profiles of 262 patients with complete follow-up data from the Cancer Genome Atlas (TCGA) database as an experimental group and selected 65 samples from the GEO dataset (of which M0 totaled 46 samples). Validated as a verification group. First, we screened the immune cell Th-17 cells related to the prognosis of COAD disease, and then identified the Th-17 cells-related hub genes by constructing co-expression network analysis (WGCNA) and lasso regression analysis (LASSO), which determined that it may be related to Th-17 cells. Six genes associated with prognosis in patients with COAD:”KRT23 ULBP2 ASRGL1 SERPINA1 SCIN SLC28A2”. Finally, we constructed a clinical prediction model and analyzed the predictive power of the model. These hub genes have been shown to be involved in the development of many diseases and are closely linked to digestive diseases. Our results suggest that the hub gene may influence the prognosis of COAD by regulating the immune infiltration of Th-17cells. Conclusions These newly discovered hub genes help to understand the mechanisms of COAD development and metastasis, thereby promoting the development of COAD and providing new therapeutic targets and biomarkers for COAD.

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Decreased SCIN expression, associated with promoter methylation, is a valuable predictor for prognosis in acute myeloid leukemia

Cited by 15 publications

References 32 publications

Endogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia

Endogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia

Endogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia

Screening of immunosuppressive cells from colorectal adenocarcinoma and identification of prognostic markers

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