Review: Beta-thalassemia and molecular chaperones

Sumera, Afshan; Radhakrishnan, Ammu Kutty; Baba, Abdul Aziz; George, Elizabeth

doi:10.1016/j.bcmd.2015.01.008

Cited by 11 publications

(11 citation statements)

References 47 publications

(96 reference statements)

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“…During late stages of erythroid differentiation, when caspases become active at the basophilic stage, HSP70 colocalizes in the nucleus with GATA-1 and protects it from cleavage. EPO has a central function in this pathway by regulating cellular localization of HSP70 11, 196 . In presence of low EPO concentration reduced nuclear HSP70 translocation results in less GATA-1 bound to HSP70.…”

Section: Mechanisms Leading To Ineffective Erythropoiesismentioning

confidence: 99%

“…It binds to free α-globin chains, but not β chains or HbA, stabilizes them and prevents their denaturation 196, 198 . AHSP is an erythroid specific chaperone primarily found in late stage erythroid precursors 196, 199 . Interactions between AHSP and free α-globin chains result in the formation of a stable complex that prevents aggregation, precipitation and autoxidation of α chains.…”

Section: Mechanisms Leading To Ineffective Erythropoiesismentioning

confidence: 99%

“…Therefore, it can be postulated that AHSP concentration is associated with disease severity. In patients with β-thalassemia inadequate concentration of AHSP results in increased hemolysis and severe anemia that requires frequent RBC transfusions 196, 199 . Studies in mice provide important information on the significance of this chaperone and its association with disease.…”

Section: Mechanisms Leading To Ineffective Erythropoiesismentioning

confidence: 99%

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What can we learn from ineffective erythropoiesis in thalassemia?

Oikonomidou

Rivella

2018

Blood Reviews

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Erythropoiesis is a dynamic process regulated at multiple levels to balance proliferation, differentiation and survival of erythroid progenitors. Ineffective erythropoiesis is a key feature of various diseases, including β-thalassemia. The pathogenic mechanisms leading to ineffective erythropoiesis are complex and still not fully understood. Altered survival and decreased differentiation of erythroid progenitors are both critical processes contributing to reduced production of mature red blood cells. Recent studies have identified novel important players and provided major advances in the development of targeted therapeutic approaches. In this review, β-thalassemia is used as a paradigmatic example to describe our current knowledge on the mechanisms leading to ineffective erythropoiesis and novel treatments that may have the potential to improve the clinical phenotype of associated diseases in the future.

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Section: Mechanisms Leading To Ineffective Erythropoiesismentioning

confidence: 99%

Section: Mechanisms Leading To Ineffective Erythropoiesismentioning

confidence: 99%

Section: Mechanisms Leading To Ineffective Erythropoiesismentioning

confidence: 99%

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What can we learn from ineffective erythropoiesis in thalassemia?

Oikonomidou

Rivella

2018

Blood Reviews

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“…With the unraveling of complex genetic and environmental factors modulating clinical severity, new potential therapeutic approaches are under development [e.g., (65,147)]: gene switching (19) that includes HbF induction by hydroxyurea; stem cell transplants; gene therapy; pharmacological targeting of defective erythropoiesis; targeting free a-chains and with a-Hb chaperones; and countering the vasculature depletion of NO from chronic hemolysis (18,19,36,102,111,133,179,189).…”

Section: Current Therapeutics Addressing Oxidative Stress and Iron Ovmentioning

confidence: 99%

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

Hirsch

Sibmooh

Fucharoen

et al. 2017

Antioxidants & Redox Signaling

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Significance: Oxidative stress and generation of free radicals are fundamental in initiating pathophysiological mechanisms leading to an inflammatory cascade resulting in high rates of morbidity and death from many inherited point mutation-derived hemoglobinopathies. Hemoglobin (Hb)E is the most common point mutation worldwide. The b E -globin gene is found in greatest frequency in Southeast Asia, including Thailand, Malaysia, Indonesia, Vietnam, Cambodia, and Laos. With the wave of worldwide migration, it is entering the gene pool of diverse populations with greater consequences than expected. Critical Issues: While HbE by itself presents as a mild anemia and a single gene for b-thalassemia is not serious, it remains unexplained why HbE/b-thalassemia (HbE/b-thal) is a grave disease with high morbidity and mortality. Patients often exhibit defective physical development, severe chronic anemia, and often die of cardiovascular disease and severe infections. Recent Advances: This article presents an overview of HbE/b-thal disease with an emphasis on new findings pointing to pathophysiological mechanisms derived from and initiated by the dysfunctional property of HbE as a reduced nitrite reductase concomitant with excess a-chains exacerbating unstable HbE, leading to a combination of nitric oxide imbalance, oxidative stress, and proinflammatory events. Future Directions: Additionally, we present new therapeutic strategies that are based on the emerging molecular-level understanding of the pathophysiology of this and other hemoglobinopathies. These strategies are designed to short-circuit the inflammatory cascade leading to devastating chronic morbidity and fatal consequences. Antioxid. Redox Signal. 26,[794][795][796][797][798][799][800][801][802][803][804][805][806][807][808][809][810][811][812][813]

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“…AHSP protein can act as a stabilizer for the α chain at the time of globin chain binding and prevents a precipitation. 62 Mice knocked-down on AHSP protein have an abnormal red blood cell production and showed shorter lifespan, allegedly caused by a relative surplus of unused globin chains. Furthermore, the phenotype was aggravated upon testing with the intermediate Thalassemia genotype, corresponding to the loss of AHSP.…”

Section: Element Factors Of Eklf Gata Gdf11 Gdf15 and Ahspmentioning

confidence: 99%

Genetic Background of β Thalassemia Modifier: Recent Update

Rujito

Sasongko

2018

J. Biomed. Transl. Res.

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Thalassemia has become major health problem among developing countries. Genetic background which contain enormous mutations and variations have lead in clinical problem differences.The genetic basis of thalassemia, beta specifically, is mutations of the gene encoding the β chain of the hemoglobin (Beta-Globin, HBB). However, today it is known that abnormalities in this gene do not necessarily determine the clinical appearance of β thalassemia patients.A set of genes has been found that can modify the primary β thalassemia disorder. Secondary modifier contains genes that have been associated with elevated levels of HbF and improvement ratio of α / β globin chain. The genes involved are HBA, HBG, BCL11A, HBS1L-MYB and other cofactor genes regulating erythropoiesis. Tertiary genetic modifier comes from other genes related to the disease severity including iron metabolism, redox activity, and clinical complications. The review aims to provide the latest updates regarding the known β Thalassemia modifier genes and some other genes involved in the changes of the clinical manifestations.

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Review: Beta-thalassemia and molecular chaperones

Cited by 11 publications

References 47 publications

What can we learn from ineffective erythropoiesis in thalassemia?

What can we learn from ineffective erythropoiesis in thalassemia?

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

Genetic Background of β Thalassemia Modifier: Recent Update

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