Analysis of the <i><scp>X</scp>mn</i>1‐<sup>G</sup>γ polymorphism in β‐thalassemia/hemoglobin <scp>E</scp> (<scp>H</scp>b<scp>E</scp>) and homozygous <scp>H</scp>b<scp>E</scp> patients with low and high levels of <scp>H</scp>b<scp>F</scp>

Prasing, Watcharee; Odawara, Toshinari; Traisathit, Patrinee; Yamashiro, Yasuhiro; Hattori, Yukio; Pornprasert, Sakorn

doi:10.1111/ijlh.12273

Cited by 6 publications

(2 citation statements)

References 11 publications

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“…This is a relevant issue that is expected to impact the criteria for recruiting patients for sirolimus-based treatments. In this context, when the relationship between the rapamycin-induction of HbF and DNA polymorphisms was analyzed, the rs368698783 LYAR (G>A) [ 113 , 114 ] and the XmnI polymorphisms [ 115 ] displayed a high association. A low relationship was found when MYB rs9399137, BCL11A rs14227407, and BCL11A rs10189857 were analyzed [ 116 ].…”

Section: Rapamycin and Biomedical Applications In Hematology: The Jou...mentioning

confidence: 99%

The Long Scientific Journey of Sirolimus (Rapamycin): From the Soil of Easter Island (Rapa Nui) to Applied Research and Clinical Trials on β-Thalassemia and Other Hemoglobinopathies

Gambari,

Zuccato,

Cosenza

et al. 2023

Biology

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In this review article, we present the fascinating story of rapamycin (sirolimus), a drug able to induce γ-globin gene expression and increased production of fetal hemoglobin (HbF) in erythroid cells, including primary erythroid precursor cells (ErPCs) isolated from β-thalassemia patients. For this reason, rapamycin is considered of great interest for the treatment of β-thalassemia. In fact, high levels of HbF are known to be highly beneficial for β-thalassemia patients. The story of rapamycin discovery began in 1964, with METEI, the Medical Expedition to Easter Island (Rapa Nui). During this expedition, samples of the soil from different parts of the island were collected and, from this material, an antibiotic-producing microorganism (Streptomyces hygroscopicus) was identified. Rapamycin was extracted from the mycelium with organic solvents, isolated, and demonstrated to be very active as an anti-bacterial and anti-fungal agent. Later, rapamycin was demonstrated to inhibit the in vitro cell growth of tumor cell lines. More importantly, rapamycin was found to be an immunosuppressive agent applicable to prevent kidney rejection after transplantation. More recently, rapamycin was found to be a potent inducer of HbF both in vitro using ErPCs isolated from β-thalassemia patients, in vivo using experimental mice, and in patients treated with this compound. These studies were the basis for proposing clinical trials on β-thalassemia patients.

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Section: Rapamycin and Biomedical Applications In Hematology: The Jou...mentioning

confidence: 99%

The Long Scientific Journey of Sirolimus (Rapamycin): From the Soil of Easter Island (Rapa Nui) to Applied Research and Clinical Trials on β-Thalassemia and Other Hemoglobinopathies

Gambari,

Zuccato,

Cosenza

et al. 2023

Biology

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“…The presence of SNPs may have implications in a disease, such as increased HbF levels in common and complex diseases or conditions, e.g., drug-induced conditions, SCD, β-thalassemia, anemia, diabetes, chronic kidney failure, malignancies, or obesity in many regions of the world, such as Europe, the Middle East, and Southeast Asia, including Malaysia [ 20 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. Several SNPs, such as rs11886868, rs766432, rs9399137, rs742144, rs9399137, rs28384513, and rs4671393, are associated with erythropoiesis and HbF augmentation ( Table 1 and Figure 2 ) [ 45 , 46 , 47 ].…”

Section: Polymorphisms Regulate the Expression Of Fetal Hemoglobinmentioning

confidence: 99%

Single Nucleotide Polymorphisms in XMN1-HBG2, HBS1L-MYB, and BCL11A and Their Relation to High Fetal Hemoglobin Levels That Alleviate Anemia

et al. 2022

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Anemia is a condition in which red blood cells and/or hemoglobin (Hb) concentrations are decreased below the normal range, resulting in a lack of oxygen being transported to tissues and organs. Those afflicted with this condition may feel lethargic and weak, which reduces their quality of life. The condition may be manifested in inherited blood disorders, such as thalassemia and sickle cell disease, whereas acquired disorders include aplastic anemia, chronic disease, drug toxicity, pregnancy, and nutritional deficiency. The augmentation of fetal hemoglobin (HbF) results in the reduction in clinical symptoms in beta-hemoglobinopathies. Several transcription factors as well as medications such as hydroxyurea may help red blood cells produce more HbF. HbF expression increases with the downregulation of three main quantitative trait loci, namely, the XMN1-HBG2, HBS1L-MYB, and BCL11A genes. These genes contain single nucleotide polymorphisms (SNPs) that modulate the expression of HbF differently in various populations. Allele discrimination is important in SNP genotyping and is widely applied in many assays. In conclusion, the expression of HbF with a genetic modifier is crucial in determining the severity of anemic diseases, and genetic modification of HbF expression may offer clinical benefits in diagnosis and disease management.

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Fetal hemoglobin regulation in β-thalassemia: heterogeneity, modifiers and therapeutic approaches

Sripichai

Fucharoen

2016

Expert Review of Hematology

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Stress erythropoiesis induces fetal hemoglobin (HbF) expression in β-thalassemias, however the level of expression is highly variable. The last decade has seen dramatic advances in our understanding of the molecular regulators of HbF production and the genetic factors associated with HbF levels, leading to the promise of new methods of the clinical induction of HbF. Areas covered: This article will review the heterogeneity and genetic modifiers of HbF and HbF induction therapy in β-thalassemia. Expert commentary: One promising curative β-thalassemia therapy is to induce HbF synthesis in β-thalassemic erythrocytes to therapeutic levels before clinical symptom occurs. Further understanding of HbF level variation and regulation is needed in order to predict the response from HbF-inducing approaches.

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Analysis of the Xmn1‐^Gγ polymorphism in β‐thalassemia/hemoglobin E (HbE) and homozygous HbE patients with low and high levels of HbF

Cited by 6 publications

References 11 publications

The Long Scientific Journey of Sirolimus (Rapamycin): From the Soil of Easter Island (Rapa Nui) to Applied Research and Clinical Trials on β-Thalassemia and Other Hemoglobinopathies

The Long Scientific Journey of Sirolimus (Rapamycin): From the Soil of Easter Island (Rapa Nui) to Applied Research and Clinical Trials on β-Thalassemia and Other Hemoglobinopathies

Single Nucleotide Polymorphisms in XMN1-HBG2, HBS1L-MYB, and BCL11A and Their Relation to High Fetal Hemoglobin Levels That Alleviate Anemia

Fetal hemoglobin regulation in β-thalassemia: heterogeneity, modifiers and therapeutic approaches

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Analysis of the Xmn1‐Gγ polymorphism in β‐thalassemia/hemoglobin E (HbE) and homozygous HbE patients with low and high levels of HbF

Cited by 6 publications

References 11 publications

The Long Scientific Journey of Sirolimus (Rapamycin): From the Soil of Easter Island (Rapa Nui) to Applied Research and Clinical Trials on β-Thalassemia and Other Hemoglobinopathies

The Long Scientific Journey of Sirolimus (Rapamycin): From the Soil of Easter Island (Rapa Nui) to Applied Research and Clinical Trials on β-Thalassemia and Other Hemoglobinopathies

Single Nucleotide Polymorphisms in XMN1-HBG2, HBS1L-MYB, and BCL11A and Their Relation to High Fetal Hemoglobin Levels That Alleviate Anemia

Fetal hemoglobin regulation in β-thalassemia: heterogeneity, modifiers and therapeutic approaches

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Analysis of the Xmn1‐^Gγ polymorphism in β‐thalassemia/hemoglobin E (HbE) and homozygous HbE patients with low and high levels of HbF