Exosome-shuttled FTO from BM-MSCs contributes to cancer malignancy and chemoresistance in acute myeloid leukemia by inducing m6A-demethylation: A nano-based investigation.

Although bone marrow mesenchymal stem cells (BM-MSCs)-derived exosomes have been reported to be closely associated with acute myeloid leukemia (AML) progression and chemo-resistance, but its detailed functions and molecular mechanisms have not been fully delineated. Besides, serum RNA m6A demethylase fat mass and obesity-associated protein (FTO)-containing exosomes are deemed as important indicators for cancer progression, and this study aimed to investigate the role of BM-MSCs-derived FTO-exosomes in regulating the malignant phenotypes of AML cells. Here, we verified that BM-MSCs-derived exosomes delivered FTO to promote cancer aggressiveness, stem cell properties and Cytosine arabinoside (Ara-C)-chemoresistance in AML cells, and the underlying mechanisms were also uncovered. Our data suggested that BM-MSCs-derived FTO-exo demethylated m6A modifications in the m6A-modified LncRNA GLCC1 to facilitate its combination with the RNA-binding protein Hu antigen R (HuR), which further increased the stability and expression levels of LncRNA GLCC1. In addition, LncRNA GLCC1 was verified as an oncogene to facilitate cell proliferation and enhanced Ara-C-chemoresistance in AML cells. Further experiments confirmed that demethylated LncRNA GLCC1 served as scaffold to facilitate the formation of the IGF2 mRNA binding protein 1 (IGF2BP1)-c-Myc complex, which led to the activation of the downstream tumor-promoting c-Myc-associated signal pathways. Moreover, our rescuing experiments validated that the promoting effects of BM-MSCs-derived FTO-exo on cancer aggressiveness and drug resistance in AML cells were abrogated by silencing LncRNA GLCC1 and c-Myc. Thus, the present firstly investigated the functions and underlying mechanisms by which BM-MSCs-derived FTO-exo enhanced cancer aggressiveness and chemo-resistance in AML by modulating the LncRNA GLCC1-IGF2BP1-c-Myc signal pathway, and our work provided novel biomarkers for the diagnosis, treatment and therapy of AML in clinic.

Efficacy Evaluation of Inflammatory Mediators in the Treatment of Multiple Myeloma with Daratumumab.

Objective: This study aimed to investigate the regulatory ability and clinical therapeutic effect of daratumumab on inflammatory mediators in patients with multiple myeloma. Method: The Multiple Myeloma Public Genetic Data Array download GSE125361 dataset was collected. The GO analysis and KEGG analysis were performed on the differential genes to elucidate the multiple myeloma cytokine-related gene pathways. Daratumumab is a CD38 monoclonal antibody used to treat multiple myeloma. Patients with newly diagnosed multiple myeloma were treated with monoclonal antibodies containing CD38, and the control group was treated with a regimen without daratumumab. The serum levels of IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ were measured in the two groups before and after treatment and the therapeutic effects of the two groups were compared. Result: The KEGG analysis showed that the Th17 cell differentiation, apoptosis, and cytokine-cytokine receptor interaction pathways were differentially expressed in multiple myeloma. The expression levels of serum IL-2, IL-6, IL-10, and TNF-α in patients in the daratumumab group were lower than those in the control group after chemotherapy. The overall effective rate of patients treated with daratumumab after chemotherapy was higher than that of the control group. Conclusion: Daratumumab can effectively improve the levels of IL-2, IL-6, IL-10, and TNF-α in patients with multiple myeloma and improve the therapeutic effect.