Hydroxyurea responsiveness in  -thalassemic patients is determined by the stress response adaptation of erythroid progenitors and their differentiation propensity

Pourfarzad, Farzin; Lindern, Marieke von; Azarkeivan, Azita; Hou, Jun; Kia, Sima Kheradmand; Esteghamat, Fatemehsadat; IJcken, Wilfred F. J. van; Philipsen, Sjaak; Najmabadi, Hossein; Grosveld, Frank

doi:10.3324/haematol.2012.074492

Cited by 50 publications

(40 citation statements)

References 63 publications

(73 reference statements)

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“…These abnormalities lead to decreased RBC production. These combined abnormalities are highly reminiscent of ineffective erythropoiesis in which FOXO3 may be a participant . Nonetheless, the precise mechanism of cell cycle and maturation defects of Foxo3 mutant erythroblasts remains unclear.…”

Section: Introductionmentioning

confidence: 99%

FOXO3‐mTOR metabolic cooperation in the regulation of erythroid cell maturation and homeostasis

et al. 2014

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Ineffective erythropoiesis is observed in many erythroid disorders including β-thalassemia and anemia of chronic disease in which increased production of erythroblasts that fail to mature exacerbate the underlying anemias. As loss of the transcription factor FOXO3 results in erythroblast abnormalities similar to the ones observed in ineffective erythropoiesis, we investigated the underlying mechanisms of the defective Foxo3−/− erythroblast cell cycle and maturation. Here we show that loss of Foxo3 results in overactivation of the JAK2/AKT/mTOR signaling pathway in primary bone marrow erythroblasts partly mediated by redox modulation. We further show that hyperactivation of mTOR signaling interferes with cell cycle progression in Foxo3 mutant erythroblasts. Importantly, inhibition of mTOR signaling, in vivo or in vitro enhances significantly Foxo3 mutant erythroid cell maturation. Similarly, in vivo inhibition of mTOR remarkably improves erythroid cell maturation and anemia in a model of β-thalassemia. Finally we show that FOXO3 and mTOR are likely part of a larger metabolic network in erythroblasts as together they control the expression of an array of metabolic genes some of which are implicated in erythroid disorders. These combined findings indicate that a metabolism-mediated regulatory network centered by FOXO3 and mTOR control the balanced production and maturation of erythroid cells. They also highlight physiological interactions between these proteins in regulating erythroblast energy. Our results indicate that alteration in the function of this network might be implicated in the pathogenesis of ineffective erythropoiesis.

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Section: Introductionmentioning

confidence: 99%

FOXO3‐mTOR metabolic cooperation in the regulation of erythroid cell maturation and homeostasis

et al. 2014

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“…Concerning the lncRNA ANRIL which is transcribed as an antisense RNA to INK4b, its elevated levels have been reported to suppress the expression of INK4A-ARF-INK4B locus in the late DNA damage response, an important mechanism to maintain genome integrity against intrinsic and extrinsic genotoxic stresses including reactive oxygen species generation, allowing negative feedback to this response [23]. Interestingly, INK4b-ARF-INK4a locus was reported to be involved in hematopoietic differentiation, proliferation, and stress response [49]. Thus, ANRIL helps the cell to return to a normal status at the completion of DNA repair [20], supporting our current findings.…”

Section: Discussionmentioning

confidence: 99%

Long non-coding RNAs MALAT1, MIAT and ANRIL gene expression profiles in beta-thalassemia patients: a cross-sectional analysis

2019

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Objectives: Beta-thalassemia (β-thal) is one of the most common genetic disorders worldwide. Multiple genetic and epigenetic mechanisms could be implicated in the pathogenesis and/or phenotype variations. We sought to explore the serum expression profile of three diseaserelated long non-coding RNAs (lncRNAs) in a sample of Egyptian β-thal patients with correlation to the patients' clinicolaboratory data. Methods: Fifty consecutive β-thal patients and 50 unrelated controls were enrolled in the study. Quantification of circulating lncRNAs; MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), MIAT (myocardial infarction associated transcript), and ANRIL (antisense noncoding RNA in the INK4 locus) was done by Real-time qRT-PCR. Results: Significant higher expression levels of the studied lncRNAs in β-thal patients compared to the controls (all P values < 0.001) were identified. There was no significant difference between β-thal-major and intermedia patients at the level of any of the studied lncRNAs. Higher MALAT1 expression profile was associated with early age at onset, early age at first blood transfusion, and a higher frequency of splenomegaly. Whereas, up-regulated MIAT levels were associated with early age at first blood transfusion. Conclusions: Taken together, the studied lncRNAs MALAT1, MIAT, and ANRIL might be implicated in β-thal pathogenesis and could provide new molecular biomarkers for β-thalassemia after validation in large-scale future studies.

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“…Therefore there is a total of 192 proteins that are significantly differentially expressed in cultures from healthy and thalassemic donors following treatment with decitabine compared to their untreated counterparts. Thalassemic cells are under considerable oxidative stress due to globin chain imbalance [20] and their expression profiles suggest that patient cells have adapted to varying degrees to these permanent stress conditions [22]. Therefore, treatment with decitabine probably modulates gene expression to a different extent in healthy and thalassemic cultures, depending on basal levels of gene expression, resulting in the relatively small overlap for ratio 1 and ratio 2 proteins.…”

Section: Samplesmentioning

confidence: 99%

Proteomic Studies for the Investigation of γ-Globin Induction by Decitabine in Human Primary Erythroid Progenitor Cultures

Theodorou

Phylactides

Katsantoni

et al. 2020

JCM

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Reactivation of γ-globin is considered a promising approach for the treatment of β-thalassemia and sickle cell disease. Therapeutic induction of γ-globin expression, however, is fraught with lack of suitable therapeutic targets. The aim of this study was to investigate the effects that treatment with decitabine has on the proteome of human primary erythroid cells from healthy and thalassemic volunteers, as a means of identifying new potential pharmacological targets. Decitabine is a known γ-globin inducer, which is not, however, safe enough for clinical use. A proteomic approach utilizing isobaric tags for relative and absolute quantitation (iTRAQ) analysis, in combination with high-pH reverse phase peptide fractionation followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), was employed to investigate the effects of decitabine treatment. Bioinformatics analysis making use of the Database for Annotation, Visualization and Integrated Discovery (DAVID) was employed for functional annotation of the 192 differentially expressed proteins identified. The data are available via ProteomeXchange with identifier PXD006889. The proteins fall into various biological pathways, such as the NF-κB signaling pathway, and into many functional categories including regulation of cell proliferation, transcription factor and DNA binding, protein stabilization, chromatin modification and organization, and oxidative stress proteins.

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Hydroxyurea responsiveness in -thalassemic patients is determined by the stress response adaptation of erythroid progenitors and their differentiation propensity

Abstract: HU in vitro, HbF induction was comparable to the increase of HbF in peripheral blood of SCD patients following HU therapy in vivo.

Cited by 50 publications

References 63 publications

FOXO3‐mTOR metabolic cooperation in the regulation of erythroid cell maturation and homeostasis

FOXO3‐mTOR metabolic cooperation in the regulation of erythroid cell maturation and homeostasis

Long non-coding RNAs MALAT1, MIAT and ANRIL gene expression profiles in beta-thalassemia patients: a cross-sectional analysis

Proteomic Studies for the Investigation of γ-Globin Induction by Decitabine in Human Primary Erythroid Progenitor Cultures

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