Rhein exerts anti-multidrug resistance in acute myeloid leukemia via targeting FTO to inhibit AKT/mTOR.

Chemotherapy failure and resistance are the leading causes of mortality in patients with acute myeloid leukemia (AML). However, the role of m6A demethylase FTO and its inhibitor rhein in AML and AML drug resistance is unclear. Therefore, this study aimed to investigate the antileukemic effect of rhein on AML and explore its potential mechanisms underlying drug resistance. Bone marrow fluid was collected to assess FTO expression in AML. The Cell Counting Kit 8 reagent was used to assess cell viability. Migration assays were conducted to assess the cell migration capacity. Flow cytometry was used to determine the apoptotic effects of rhein and western blot analysis was used to detect protein expression. Online SynergyFinder software was used to calculate the drug synergy scores. The in-vivo antileukemic effect of rhein was assessed in an AML xenograft mouse model. We analyzed different types of AML bone marrow specimens to confirm that FTO is overexpressed in AML, particularly in cases of multidrug resistance. Subsequently, we conducted in-vivo and in-vitro investigations to explore the pharmacological activity and mechanism of rhein in AML and AML with multidrug resistance. The findings demonstrated that rhein effectively suppressed the proliferation and migration of AML cells in a time- and dose-dependent manner and induced apoptosis. Rhein targets FTO, inhibits the AKT/mTOR pathway, and exhibits synergistic antitumor effects when combined with azacitidine. This study elucidates the significant role of FTO and its inhibitor rhein in AML and AML with multidrug resistance, providing new insights for overcoming multidrug resistance in AML.

Acute myeloid leukemia (AML)-derived mesenchymal stem cells induce chemoresistance and epithelial-mesenchymal transition-like program in AML through IL-6/JAK2/STAT3 signaling.

Acute myeloid leukemia (AML) has a high rate of treatment failure due to increased prevalence of therapy resistance. Mesenchymal stem cells (MSCs) in the leukemia microenvironment contribute to chemoresistance in AML, but the specific mechanism remains unclear. The critical role of the epithelial-mesenchymal transition (EMT)-like profile in AML chemoresistance has been gradually recognized. However, there is no research to suggest that the AML-derived bone marrow mesenchymal stem cells (AML-MSCs) induce the EMT program in AML thus far. We isolated AML-MSCs and cocultured them with AML cells. We found that AML-MSCs induced a significant mesenchymal-like morphology in drug-resistant AML cells, but it was scarce in parental AML cells. The AML-MSCs promoted growth of AML cells in the presence or absence of chemotherapeutics in vitro and in vivo. Acute myeloid leukemia MSCs also induced EMT marker expression in AML cells, especially in chemoresistant AML cells. Mechanistically, AML-MSCs secreted abundant interleukin-6 (IL-6) and upregulated IL-6 expression in AML cells. Acute myeloid leukemia cells upregulated IL-6 expression in AML-MSCs in turn. Meanwhile, AML-MSCs activated the JAK2/STAT3 pathway in AML cells. Two JAK/STAT pathway inhibitors counteracted the AML-MSCs induced morphology change and EMT marker expression in AML cells. In conclusion, AML-MSCs not only promote the emergence of chemoresistance but also enhance it once AML acquires chemoresistance. AML-MSCs induce EMT-like features in AML cells; this phenotypic change could be related to chemoresistance progression. AML-MSCs induce the EMT-like program in AML cells through IL-6/JAK2/STAT3 signaling, which provides a therapeutic target to reverse chemoresistance in AML.

The m6A modulator-mediated cytarabine sensitivity and immune cell infiltration signature in acute myeloid leukemia.

PURPOSE: The study aims to investigate the impact of m6A modulators on drug resistance and the immune microenvironment in acute myeloid leukemia (AML). The emergence of drug resistance is a significant factor that contributes to relapse and refractory AML, leading to a poor prognosis. METHODS: The AML transcriptome data were retrieved from the TCGA database. The "oncoPredict" R package was utilized to assess the sensitivity of each sample to cytarabine (Ara-C) and classify them into distinct groups. Differential expression analysis was performed to identify m6A modulators differentially expressed between the two groups. Select Random Forest (RF) to build a predictive model. Model performance was evaluated using calibration curve, clinical decision curve, and clinical impact curve. The impacts of METTL3 on Ara-C sensitivity and immune microenvironment in AML were examined using GO, KEGG, CIBERSORT, and GSEA analyses. RESULTS: Seventeen out of 26 m6A modulators exhibited differential expression between the Ara-C-sensitive and resistant groups, with a high degree of correlation. We selected the 5 genes with the highest scores in the RF model to build a reliable and accurate prediction model. METTL3 plays a vital role in m6A modification, and further analysis shows its impact on the sensitivity of AML cells to Ara-C through its interaction with 7 types of immune-infiltrating cells and autophagy. CONCLUSION: This study utilizes m6A modulators to develop a prediction model for the sensitivity of AML patients to Ara-C, which can assist in treating AML drug resistance by targeting mRNA methylation.

Conflict or Collaboration-The Impact of Knowledge Endowment Heterogeneity on Remix in Open Collaborative Communities.

With the emergence of online open platforms and communities, remix has drawn much attention as an essential source of innovation whereby the knowledge endowment of online community users plays a crucial role. This study constructs a structural equation model to explore the impact of user knowledge endowment heterogeneity on remix through the mediating effect of their collaborative psychology. In this empirical study, we collected 25,032 pieces of data from Thingiverse (a 3D printing community) users and their published designs. The findings are as follows. Explicit knowledge endowment heterogeneity has a positive impact on the quantity of remix but a negative impact on its quality. Likewise, the implicit knowledge endowment heterogeneity positively affects the quantity of remix but has no significant effect on its quality. Users' conflicting psychology plays a mediating role between knowledge endowment heterogeneity and remix, while their collaborative psychology negatively mediates merely between explicit knowledge endowment heterogeneity and remix quality. By unraveling the relationship between user knowledge endowment heterogeneity, collaborative psychology, and remix, this study is significant in understanding users' remix process in open collaborative communities and illuminating their psychological mechanism in this process.

PLCB4 upregulation is associated with unfavorable prognosis in pediatric acute myeloid leukemia.

Phospholipase C (PLC) is a membrane-associated enzyme that regulates several cellular behaviors including cell motility, growth, transformation and differentiation. PLC is involved in cancer migration, invasion and drug resistance. However, the expression status and prognostic role of PLCB4 in acute myeloid leukemia (AML) remain unclear. In the present study, the complete clinical and mRNA expression data of 285 pediatric patients with de novo AML were obtained from the Therapeutically Available Research to Generate Effective Treatments database. The association between PLCB4 expression and clinical and molecular features was explored. The expression of PLCB4 was significantly higher in patients with AML who relapsed compared with those with long-term complete remission. Patients with PLCB4 upregulation had significantly lower overall survival (OS) and event free survival (EFS) rate compared with those with low PLCB4 expression. Multivariate Cox's regression analyses demonstrated that high PLCB4 expression was an independent risk factor of adverse OS (P<0.01; HR, 2.081) and EFS (P<0.01; HR, 2.130). Following stratification analysis according to transplant status in cases of first complete remission, the patients with high expression of PLCB4 had significantly lower OS and EFS rate in the chemotherapy group, but not the stem cell transplant group. Furthermore, PLCB4-associated genes were identified using Spearman's rank correlation analysis. KEGG pathway analysis revealed that PLCB4 and its associated genes were mainly involved in three potential pathways, including the Rap1 signaling pathway. Overall, the findings of the present study suggest that increased PLCB4 expression is associated with poor clinical outcome in pediatric patients with AML, and thus may represent a potential prognostic biomarker and therapeutic target for AML.