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OPINION STATEMENT: Multiple myeloma (MM) is the second most common hematological malignant (HM) tumor, and a large proportion of patients still suffer from treatment failure and a poor prognosis despite the use of some newly approved drugs, a deeper understanding of the underlying mechanism is still needed. Ferroptosis is a new form of programmed cell death (PCD) that is different from other traditional forms of cell death such as apoptosis, necrosis and autophagy. With the continuous deepening of research on ferroptosis, ferroptosis has been found to be closely related to MM. This article reviews the regulatory mechanism of ferroptosis and research progress on ferroptosis in MM, providing a new theoretical basis and strategies for the diagnosis and treatment of MM.
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Ferroptose , Mieloma Múltiplo , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/diagnóstico , Ferroptose/efeitos dos fármacos , Humanos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Animais , Suscetibilidade a Doenças , Transdução de Sinais , Gerenciamento Clínico , Terapia de Alvo Molecular , Biomarcadores TumoraisRESUMO
OPINION STATEMENT: Leukemia is a type of hematological malignancy (HM) caused by uncontrolled proliferation, apoptosis, and differentiation of hematopoietic stem cells (HSCs). Leukemia cells proliferate greatly in the bone marrow (BM), infiltrate other tissues and organs, and affect the normal hematopoietic function. Although the emergence of new targeted agents and immune agents has improved the prognosis of patients, due to the complex pathogenic factors and heterogeneity of leukemia, there are still some patients with poor prognosis. Recent studies have shown that silent information regulator 1 (SIRT1) is involved in the proliferation, apoptosis, metabolism, and senescence of leukemia cells. As a double-edged sword in leukemia cells, SIRT1 can both promote and inhibit the growth of leukemia cells. Since its mechanism of action has not been elucidated, it is urgent to explore the regulatory mechanism of SIRT1 in leukemia. In this review, we discussed the mechanisms of SIRT1 in different aspects of leukemia, providing a theoretical basis for the treatment of patients with leukemia.
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Leucemia , Sirtuína 1 , Humanos , Sirtuína 1/metabolismo , Leucemia/metabolismo , Leucemia/etiologia , Leucemia/terapia , Leucemia/patologia , Apoptose , Animais , Transdução de Sinais , Proliferação de Células , Prognóstico , Células-Tronco Hematopoéticas/metabolismo , Suscetibilidade a Doenças , Gerenciamento ClínicoRESUMO
OPINION STATEMENT: Pyroptosis is a kind of programmed cell death dependent on the caspase pathway that is different from apoptosis and necrosis. Recent studies have shown that pyroptosis can be involved in the pathological processes of many diseases, such as cancers, atherosclerosis, diabetic nephropathy, and blood diseases. However, the specific mechanisms by which pyroptosis participates in the occurrence and development of hematological malignant tumors still need further exploration. This article reviews the characteristics of pyroptosis and the regulatory mechanisms promoting or inhibiting pyroptosis and discusses the role of pyroptosis in hematological malignant tumors, which could provide ideas for the clinical treatment of such tumors in the future.
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Neoplasias Hematológicas , Piroptose , Humanos , Piroptose/fisiologia , Apoptose , Necrose , Neoplasias Hematológicas/etiologia , Neoplasias Hematológicas/terapiaRESUMO
Mesenchymal stem cells (MSCs) are a subset of multifunctional stem cells with self-renewal and multidirectional differentiation properties that play a pivotal role in tumor progression. MSCs are reported to exert biological functions by secreting specialized vesicles, known as exosomes, with tumor cells. Exosomes participate in material and information exchange between cells and are crucial in multiple physiological and pathological processes. This study provides a comprehensive overview of the roles, mechanisms of action and sources of MSC exosomes in hematological malignancies, and different tumor types.
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Exossomos/metabolismo , Neoplasias Hematológicas/genética , Células-Tronco Mesenquimais/metabolismo , Neoplasias Hematológicas/patologia , HumanosRESUMO
ABSTRACT: Ferroptosis is an iron-dependent cell death pathway that is different from apoptosis, pyroptosis, and necrosis. The main characteristics of ferroptosis are the Fenton reaction mediated by intracellular free divalent iron ions, lipid peroxidation of cell membrane lipids, and inhibition of the anti-lipid peroxidation activity of intracellular glutathione peroxidase 4 (GPX4). Recent studies have shown that ferroptosis can be involved in the pathological processes of many disorders, such as ischemia-reperfusion injury, nervous system diseases, and blood diseases. However, the specific mechanisms by which ferroptosis participates in the occurrence and development of acute leukemia still need to be more fully and deeply studied. This article reviews the characteristics of ferroptosis and the regulatory mechanisms promoting or inhibiting ferroptosis. More importantly, it further discusses the role of ferroptosis in acute leukemia and predicts a change in treatment strategy brought about by increased knowledge of the role of ferroptosis in acute leukemia.
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Ferroptose , Leucemia Mieloide Aguda , Humanos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Morte Celular , Ferro/metabolismoRESUMO
BACKGROUND: BM-MSCs play an important role in cancer development through the release of cytokines or exosomes. Studies have shown that extracellular exosomes derived from BM-MSCs are a key pro-invasive factor. However, how BM-MSC-exos influence AML cell proliferation, invasion and chemoresistance remains poorly understood. METHODS: We isolated exosomes from BM-MSCs and used electron microscopy, particle size separation and western blots to identify the exosomes. The invasion of leukemia cells was observed with a transwell assay. The stemness traits and chemoresistance of the leukemia cells were detected by FCM, colony formation and CCK-8 assays. TCGA database was used to investigate the prognostic relevance of S100A4 and its potential role in AML. RESULTS: In this study, we found that BM-MSC-exos increased the metastatic potential, maintained the stemness and contributed to the chemoresistance of leukemia cells. Mechanistically, BM-MSC-exos promoted the proliferation, invasion and chemoresistance of leukemia cells via upregulation of S100A4. Downregulating S100A4 clearly suppressed the proliferation, invasion, and chemoresistance of leukemia cells after treatment with BM-MSC-exos. Bioinformatic analysis with data in TCGA database showed that S100A4 was associated with poor prognosis in AML patients, and functional enrichment revealed its involvement in the processes of cell-cell adhesion and cytokine regulation. CONCLUSIONS: S100A4 is vital in the BM-MSC-exo-driven proliferation, invasion and chemoresistance of leukemia cells and may serve as a potential target for leukemia therapy.
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BACKGROUND: Knowledge of immune cell phenotypes, function, and developmental trajectory in acute myeloid leukemia (AML) microenvironment is essential for understanding mechanisms of evading immune surveillance and immunotherapy response of targeting special microenvironment components. METHODS: Using a single-cell RNA sequencing (scRNA-seq) dataset, we analyzed the immune cell phenotypes, function, and developmental trajectory of bone marrow (BM) samples from 16 AML patients and 4 healthy donors, but not AML blasts. RESULTS: We observed a significant difference between normal and AML BM immune cells. Here, we defined the diversity of dendritic cells (DC) and macrophages in different AML patients. We also identified several unique immune cell types including T helper cell 17 (TH17)-like intermediate population, cytotoxic CD4+ T subset, T cell: erythrocyte complexes, activated regulatory T cells (Treg), and CD8+ memory-like subset. Emerging AML cells remodels the BM immune microenvironment powerfully, leads to immunosuppression by accumulating exhausted/dysfunctional immune effectors, expending immune-activated types, and promoting the formation of suppressive subsets. CONCLUSION: Our results provide a comprehensive AML BM immune cell census, which can help to select pinpoint targeted drug and predict efficacy of immunotherapy.