Homoharringtonine- (HHT-) based HHT, aclarubicin, and cytarabine (HAA) induction regimen is the first-line therapy for nonelder acute myeloid leukemia (AML) patients in China. However, drug resistance is a new challenge, and little attention has been devoted to excavating resistant mechanisms. This study used the classic method to construct six HHT-resistant cell lines with a gradually increasing resistance index (RI) to discover HHT drug resistance mechanisms dynamically. After HHT resistance, the cell growth rate decreased, cell cycle delayed, and P-glycoprotein (p-gp, CD243) expression levels increased. Furthermore, we explored the changes in transcriptomics between HHT-sensitive and HHT-resistant cells using RNA-sequence. Through Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and hub gene analyses, we found that immune activity, especially G-protein coupled receptor (GPR) and related molecules, may mediate HHT resistance. Moreover, Calcitonin Receptor-Like (CALCRL) and G Protein Subunit Alpha I1 (GNAI1), which belong to GPRs, were stimulated in HHT-resistant cell strains in vitro and vivo, indicating that they may play a critical role in HHT resistance. In addition, these two genes have prognostic significance for AML patients. Taken together, we successfully constructed HHT-resistant cell lines with dynamic RIs and explored the resistance mechanisms, which will help identify new drugs for HHT-resistant AML patients.
Abstract The hallmarks of stem cells, such as proliferation, self-renewal, development, differentiation, and regeneration, are critical to maintain stem cell identity which is sustained by genetic and epigenetic factors. Super-enhancers (SEs), which consist of clusters of active enhancers, play a central role in maintaining stemness hallmarks by specifically transcriptional model. The SE-navigated transcriptional complex, including SEs, non-coding RNAs, master transcriptional factors, Mediators and other co-activators, forms phase-separated condensates, which offers a toggle for directing diverse stem cell fate. With the burgeoning technologies of multiple-omics applied to examine different aspects of SE, we firstly raise the concept of “super-enhancer omics”, inextricably linking to Pan-omics. In the review, we discuss the spatiotemporal organization and concepts of SEs, and describe links between SE-navigated transcriptional complex and stem cell features, such as stem cell identity, self-renewal, pluripotency, differentiation and development. We also elucidate the mechanism of stemness and oncogenic SEs modulating cancer stem cells via genomic and epigenetic alterations hijack in cancer stem cell. Additionally, we discuss the potential of targeting components of the SE complex using small molecule compounds, genome editing, and antisense oligonucleotides to treat SE-associated organ dysfunction and diseases, including cancer. This review also provides insights into the future of stem cell research through the paradigm of SEs.
Immunotherapy for hematological malignancies is a rapidly advancing field that has gained momentum in recent years, primarily encompassing chimeric antigen receptor T-cell (CAR-T) therapies, immune checkpoint inhibitors, and other modalities. However, its clinical efficacy remains limited, and drug resistance poses a significant challenge. Therefore, novel immunotherapeutic targets and agents need to be identified. Recently, N6-methyladenosine (m6A), the most prevalent RNA epitope modification, has emerged as a pivotal factor in various malignancies. Reportedly, m6A mutations influence the immunological microenvironment of hematological malignancies, leading to immune evasion and compromising the anti-tumor immune response in hematological malignancies. In this review, we comprehensively summarize the roles of the currently identified m6A modifications in various hematological malignancies, with a particular focus on their impact on the immune microenvironment. Additionally, we provide an overview of the research progress made in developing m6A-targeted drugs for hematological tumor therapy, to offer novel clinical insights.
Background: Recently, an increasing number of studies have suggested dual-specificity phosphatase 23 (DUSP23) is a critical factor in the development of diffuse connective tissue disease and may be a valuable biomarker for primary human cancers. However, there is a lack of comprehensive studies on the prognostic significance of DUSP23 expression in acute myeloid leukemia (AML). Methods: RNA sequencing data from The Cancer Genome Atlas (TCGA) (AML = 173), Genotype-Tissue Expression (GTEx) (healthy controls = 70) and GEO (AML = 461, healthy controls = 76) databases were used to compare DUSP23 expression between AML patients and healthy controls. The overall survival (OS) of DUSP23 in AML was evaluated using Kaplan-Meier Cox regression. Furthermore, univariate Cox regression and multivariate Cox regression analysis were used to determine whether DUSP23 was an independent prognostic factor for AML. We then verified the expression level and prognostic significance of DUSP23 in our cohort (AML = 128, healthy controls = 31). In addition, functional enrichment analysis of DUSP23-related DEGs was performed through gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) network analysis. Results: The expression level of DUSP23 is significantly higher in AML patients than in healthy controls in TCGA, GTEx, GEO databases and our cohort. By multivariate analysis, high expression of DUSP23 is a poor prognostic indicator of OS in the TCGA database. Next, we verified the role of DUSP23 as an adverse prognostic biomarker in our cohort. Enrichment analysis of related genes showed that DUSP23 may regulate important signal pathways in hematological tumors including the MAPK pathways. It is suggested by the PPI network that DUSP23, along with IMP3, MRPL4, MRPS12, POLR2L, and ATP5F1D may play a role in the process of AML. Conclusion: The study demonstrated high expression of DUSP23 could serve as a poor independent prognostic biomarker in AML. Keywords: DUSP23, expression, prognosis, AML, bioinformatics
Background: Acute myeloid leukemia (AML) is a heterogeneous disease, for which identifying reliable prognostic markers is critical for accurate clinical prognosis and treatment optimization. The inhibition of emopamil-binding protein gene (EBP) expression has been demonstrated to induce cancer cell death via depleting downstream sterols. Nevertheless, no comprehensive studies have been conducted specifically in tumors, including AML.
Emerging evidence shows that the aberrantly expressed cyclic AMP responsive element-binding protein (CREB) is associated with tumor development and progression in several cancers. Spindle and kinetochore-associated protein 2 (SKA2) is essential for regulating the progress of mitosis. In this study, we evaluate in vitro and in vivo the functional relationship between CREB and SKA2 in renal cell carcinoma (RCC). Suppressing and replenishing CREB levels were used to manipulate SKA2 expression, observing the effects on RCC cell lines. Computational prediction and ChIP assay identified that CREB targeted ska2 by binding its CRE sequence in the human genome. Overexpression of CREB reversed the inhibited cell growth following siSKA2 treatment, and reduced the number of cells holding in mitosis. Decreased expression of CREB suppressed RCC cell growth and xenograft tumor formation, accompanied by reduced expression of SKA2. In RCC tumor samples from patients, mRNA for SKA2 were plotted near those of CREB in each sample, with significantly increased immunohistochemical staining of higher SKA2 and CREB in the higher TNM stages. The study adds evidence that CREB, a tumor oncogene, promotes RCC proliferation. It probably achieves this by increasing SKA2 expression.
Recent studies have suggested that CD300A was an oncogene in acute myeloid leukemia (AML) development. However, the clinical relevance and biological insight into CD300A expression in AML are still not well understood. The present study aimed to examine the expression characteristics of CD300A in AML and confirmed its clinical significance for AML.Quantification of the CD300A transcript was performed in 119 AML patients by real-time quantitative PCR in bone marrow blasts. The predictive significance of CD300A expression on the clinical outcomes of AML was assessed using overall survival (OS) and relapse-free survival (RFS). The published Cancer Genome Atlas (TCGA) data were used as an external validation for survival analysis and pathway analyses.In comparison with monocytes from healthy peripheral blood cells, the expression levels of CD300A in AML cells were higher. Patients in the intermediate and adverse risk categories by WHO criteria (2018) had higher CD300A expression levels than those in the favorable risk category (p < 0.001). AML patients with high expression of CD300A had a higher early death rate (p = 0.029), lower complete remission rate (p = 0.042), higher death rate (p < 0.001) and relapse rate (p = 0.002), and shorter OS (p < 0.0001) and RFS (p < 0.0001). Through multivariable analysis, high CD300A expression in AML was also an independent poor prognostic factor. The CAMP and CGMP-PKG signaling pathways may be stimulated by increased CD300A expression levels, which may be important for the development of AML.The expression levels of CD300A were associated with risk stratification and the clinical relevance of AML. High CD300A expression may act as an independent adverse prognostic factor for OS and RFS in AML.
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