Unlabelled: Acute myeloid leukemia (AML), an aggressive hematopoietic malignancy, exhibits poor prognosis and a high recurrence rate largely because of primary and secondary drug resistance. Elevated serum IL6 levels have been observed in patients with AML and are associated with chemoresistance. Chemoresistant AML cells are highly dependent on oxidative phosphorylation (OXPHOS), and mitochondrial network remodeling is essential for mitochondrial function. However, IL6-mediated regulation of mitochondrial remodeling and its effectiveness as a therapeutic target remain unclear. We aimed to determine the mechanisms through which IL6 facilitates the development of chemoresistance in AML cells. IL6 upregulated mitofusin 1 (MFN1)-mediated mitochondrial fusion, promoted OXPHOS, and induced chemoresistance in AML cells. MFN1 knockdown impaired the effects of IL6 on mitochondrial function and chemoresistance in AML cells. In an MLL::AF9 fusion gene-induced AML mouse model, IL6 reduced chemosensitivity to cytarabine (Ara-C), a commonly used antileukemia drug, accompanied by increased MFN1 expression, mitochondrial fusion, and OXPHOS status. In contrast, anti-IL6 antibodies downregulated MFN1 expression, suppressed mitochondrial fusion and OXPHOS, enhanced the curative effects of Ara-C, and prolonged overall survival. In conclusion, IL6 upregulated MFN1-mediated mitochondrial fusion in AML, which facilitated mitochondrial respiration, in turn, inducing chemoresistance. Thus, targeting IL6 may have therapeutic implications in overcoming IL6-mediated chemoresistance in AML.
Implications: IL6 treatment induces MFN1-mediated mitochondrial fusion, promotes OXPHOS, and confers chemoresistance in AML cells. Targeting IL6 regulation in mitochondria is a promising therapeutic strategy to enhance the chemosensitivity of AML.
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http://dx.doi.org/10.1158/1541-7786.MCR-23-0382 | DOI Listing |
Exp Cell Res
January 2025
Cardiovascular Center, College of Medicine, University of Cincinnati, Ohio-45267, United States of America; School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur-613401, Tamil Nadu, India. Electronic address:
Multiple forms of cell death contribute significantly to cardiovascular pathologies, negatively impacting cardiac remodeling and leading to heart failure. While myocardial cell death has been associated with PM induced cardiotoxicity, the temporal dynamics of various cell death forms, such as apoptosis, ferroptosis, necroptosis, and pyroptosis, in relation to inflammatory processes, remain underexplored. This study examines the time-dependent onset and progression of these cell death pathways in the myocardium and their correlation with inflammation in a Wistar rat model.
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January 2025
Division of Hematology, Brigham and Women's Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA. Electronic address:
Single-cell RNA sequencing (scRNA-seq) enables detailed characterization of cell states but often lacks insights into tissue clonal structures. Here, we present a protocol to probe cell states and clonal information simultaneously by enriching mitochondrial DNA (mtDNA) variants from 3'-barcoded full-length cDNA. We describe steps for input library preparation, mtDNA enrichment, PCR product cleanup, and paired-end sequencing.
View Article and Find Full Text PDFHeliyon
July 2024
School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
Metformin (MET), a commonly prescribed medication for managing type 2 diabetes, has demonstrated various beneficial effects beyond its primary anti-diabetic efficacy. However, the mechanism underlying MET activity and its distribution within organelles remain largely unknown. In this study, we integrate multiple technologies, including chemical labeling, immunostaining, and high-resolution microscopy imaging, to visualize the accumulation of MET in organelles of cultured cells.
View Article and Find Full Text PDFJ Cachexia Sarcopenia Muscle
February 2025
Department of Cardiovascular Sciences, College of Life Sciences, University of Leicester, Leicester, UK.
Background: Obesity is a chronic disease associated with increased risk of multiple metabolic and mental health-related comorbidities. Recent advances in obesity pharmacotherapy, particularly with glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), have the potential to transform obesity and type 2 diabetes mellitus (T2DM) care by promoting marked weight loss, improving glycaemic control and addressing multiple obesity-related comorbidities, with added cardio-renal benefits. Dual agonists combining GLP-1 with other enteropancreatic hormones such as glucose-dependent insulinotropic polypeptide (GIP) have also been developed in recent years, leading to greater weight loss than using GLP-1 RAs alone.
View Article and Find Full Text PDFJ Transl Med
January 2025
Department of Pathology, Renmin Hospital of Wuhan University, 238 Jiefang-Road, Wuchang District, Wuhan, 430060, P. R. China.
With breast cancer being the most common tumor among women in the world today, it is also the leading cause of cancer-related deaths. Standard treatments include chemotherapy, surgery, endocrine therapy, and targeted therapy. However, the heterogeneity, drug resistance, and poor prognosis of breast cancer highlight an urgent need for further exploration of its underlying mechanisms.
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