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Gene expression profiling in myelodysplastic syndrome patients treated with deferasirox

ABSTRACT: Deferasirox (DFX) is an oral iron chelator used to reduce iron overload caused by frequent red blood cell transfusions in anemic myelodysplastic syndrome (MDS) patients. To study molecular mechanisms by which DFX improves outcome in MDS, we analyzed gene expression patterns in MDS patients before and after DFX therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160727 | GEO | 2020/11/04

REPOSITORIES: GEO

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Genome-wide transcriptomics leads to the identification of deregulated genes after deferasirox therapy in low-risk MDS patients

Project description:The iron chelator deferasirox is widely used in patients with iron overload. Patients with low-grade myelodysplastic syndromes (MDS) get transfusion dependency and need to be treated with deferasirox to avoid iron overload. Moreover, in some patients an increase in both erythroid and platelets have been observed after deferasirox therapy. However, the mechanisms involved in these clinical findings are poorly understood. The aim of this work was to analyze, in patients treated with deferasirox, the changes in the gene expression profile after receiving the treatment. A total of fifteen patients with the diagnosis of low-grade MDS were studied. Microarrays were carried out in RNA from peripheral blood before and after 14 weeks of deferasirox therapy. Changes in 1,457 genes and 54 miRNAs were observed: deferasirox induced the downregulation of genes related to the Nf kB pathway leading of an overall inactivation of this pathway. In addition, the iron chelator also downregulated gamma interferon. Altogether these changes could be related to the improvement of erythroid response observed in these patients after therapy. Moreover, the inhibition of NFE2L2/ NRF2, which was predicted in silico, could be playing a critical role in the reduction of reactive oxygen species (ROS). Of note, miR-125b, overexpressed after deferasirox treatment, could be involved in the reduced inflammation and increased hematopoiesis observed in the patients after treatment. In summary this study shows, for the first time, the mechanisms that could be governing deferasirox impact in vivo.

2019-12-13 | GSE141958 | GEO

Oxidative stress in myelodysplastic syndromes

Project description:Control of oxidative stress in the bone marrow (BM) is key for maintaining the balance between self-renewal, proliferation, and differentiation of hematopoietic cells. Breakdown of this regulation can lead to diseases characterized by BM failure such as the myelodysplastic syndromes (MDS). To better understand the role of oxidative stress in MDS development, we compared protein carbonylation as an oxidative stress marker in BM of patients with MDS and control subjects, and also patients with MDS under treatment with the iron chelator deferasirox.

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Deferasirox, an iron chelator, impacts myeloid differentiation by modulating NF-kB activity via mitochondrial ROS

Project description:Deferasirox (DFX) can improve erythropoiesis in patients with MDS. We sought to test how these changes occur and whether myelopoiesis broadly is affected by analyzing neutrophils and neutrophil precursors treated with DFX.

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Deferasirox in Treating Iron Overload Caused By Blood Transfusions in Patients With Hematologic Malignancies

Project description:RATIONALE: Deferasirox may remove excess iron from the body caused by blood transfusions. PURPOSE: This clinical trial studies deferasirox in treating iron overload caused by blood transfusions in patients with hematologic malignancies.

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Iron Chelator Deferasirox Reduces Candida albicans Invasion of Oral Epithelial Cells and Infection Levels in Murine Oropharyngeal Candidiasis

Project description:Candida albicans, the causative agent of mucosal infections including oropharyngeal candidiasis (OPC) as well as bloodstream infections is becoming increasingly resistant to existing treatment options. In the absence of novel drug candidates, drug repurposing aimed at using existing drugs to treat off label diseases is a promising strategy. C. albicans requires environmental iron for survival and virulence while host nutritional immunity deploys iron-binding proteins to sequester iron and reduce fungal growth. Here we evaluated the role of iron-limitation using Deferasirox (an FDA approved iron chelator for treatment of patients with iron overload) during murine OPC; and assessed Deferasirox-treated C. albicans for its interaction with human oral epithelial (OE), neutrophils, and antimicrobial peptides. Therapeutic Deferasirox treatment significantly reduced salivary iron levels while a non-significant reduction in fungal burden was observed. Preventive treatment that allowed for two additional days of drug administration in our murine model, resulted in significant reduction of C. albicans colony forming units (CFU)/g of tongue tissue, a significant reduction in salivary iron levels, and significantly reduced neutrophil-mediated inflammation. C. albicans harvested from tongues of animals undergoing preventive treatment had differential expression of 106 genes, including those involved in iron metabolism, adhesion, and response to host innate immunity. Moreover, Deferasirox-treated C. albicans cells had two-fold reduction in survival in neutrophil phagosomes (with greater susceptibility to oxidative stress); and reduced adhesion and invasion of OE cells, in vitro. Thus Deferasirox treatment has the potential to alleviate OPC by affecting C. albicans gene expression and reducing virulence

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A variant erythroferrone disrupts iron homeostasis in SF3B1-mutated myelodysplastic syndrome (RNA-Seq)

Project description:Myelodysplastic syndromes (MDS) with ring sideroblasts are hematopoietic stem celldisorders with erythroid dysplasia and mutations in the SF3B1 splicing factor gene. MDS patientswith SF3B1 mutations often accumulate excessive tissue iron, even in the absence oftransfusions, but the mechanisms that are responsible for their parenchymal iron overload areunknown. Body iron content, tissue distribution, and the supply of iron for erythropoiesis arecontrolled by the hormone hepcidin, which is regulated by erythroblasts through secretion of theerythroid hormone erythroferrone (ERFE). Here, we identified an alternative ERFE transcript inMDS patients with the SF3B1 mutation. Induction of this ERFE transcript in primary SF3B1-mutated bone marrow erythroblasts generated a variant protein that maintained the capacity tosuppress hepcidin transcription. Plasma concentrations of ERFE were higher in MDS patientswith a SF3B1 gene mutation than in patients with SF3B1 wild-type MDS. Thus, hepcidinsuppression by a variant erythroferrone is likely responsible for the increased iron loading inpatients with SF3B1-mutated MDS, suggesting that ERFE could be targeted to prevent ironmediated toxicity. The expression of the variant ERFE transcript that was restricted to SF3B1-mutated erythroblasts decreased in lenalidomide-responsive anemic patients, identifying variantERFE as a specific biomarker of clonal erythropoiesis.

2019-06-18 | GSE132836 | GEO

RNA-seq of Highly Metastatic and Lowly Metastatic 4T1 Single Clones Treated with Iron Chelator Deferasirox (DFX)

Project description:Using bulk RNA-seq, the transcriptional profile of two cell lines with high or low metastatic properties derived from single clones of the murine 4T1 cell line treated or untreated with iron chelator DFX was analyzed in order to determine the mechanism underlying the inhibition preference of DFX for highly metastatic 4T1 cells.

2022-11-16 | GSE218133 | GEO

Combination of iron deprivation and chemotherapies treatments in breast cancer xenografts

Project description:To ensure their high proliferation rate, tumor cells display an iron metabolic disorder with increased iron needs, making them more susceptible to iron deprivation. This vulnerability could be a therapeutic target. In breast cancers, the development of new therapeutic approaches is urgently needed for patients with triple negative tumors which frequently relapse after chemotherapy and suffer from a lack of targeted therapies. Anticancer activity of iron chelator deferasirox (DFX) assessed in monotherapy do not appear to be effective enough to treat breast cancer progression. In this work, we demonstrated that DFX synergizes with standard chemotherapeutic agents such as with doxorubicin, cisplatin and carboplatin to inhibit cell proliferation and induce apoptosis and autophagy in TNBC cell lines. Moreover, the combination of DFX with doxorubicin and cyclophosphamide allowed to delay or avoid recurrences in breast cancer patient-derived xenografts without increasing the side-effects of chemotherapies alone or altering global iron storage of mice. Antitumor synergy of DFX and doxorubicin involves down-regulation of PI3K and NF-κB pathways. Furthermore, as TNBC patients with low iron tumor dynamic in their tumor present a good prognosis, we thought that iron deprivation mediated by iron chelators may all the more increase the effectiveness of conventional chemotherapies for TNBC treatments.

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