title: Increased oxidative metabolism is associated with erythroid precursor expansion in β0-thalassaemia/Hb E disease.
abstract: Erythropoiesis in β0-thalassaemia/Hb E patients, the most common variant form of β-thalassaemia in Southeast Asia, is characterized by accelerated differentiation and over-expansion of erythroid precursor cells. The mechanism driving this accelerated expansion and differentiation remain unknown. To address this issue a proteomic analysis was undertaken to firstly identify proteins differentially expressed during erythroblast differentiation and a second analysis was undertaken to identify proteins differentially expressed between β0-thalassaemia/Hb E erythroblasts and control erythroblasts. The majority of proteins identified as being differentially expressed between β0-thalassaemia/Hb E and control erythroblasts were constituents of the glycolysis/TCA pathway and levels of oxidative stress correlated with the degree of erythroid expansion. A model was constructed linking these observations with previous studies showing increased phosphorylation of ERK1/2 in thalassemic erythroblasts which predicted the increased activation of PKA, PKB and PKC which Western analysis confirmed. Inhibition of PKA or PKC reduced β0-thalassaemia/Hb E erythroblast differentiation and/or expansion. We propose that increased expansion and differentiation of β0-thalassaemia/Hb E erythroblasts occur as a result of feedback loops acting through increased oxidative metabolism.
authors.affiliation: Molecular Pathology Laboratory, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand.
authors.forename: Amporn
authors.initials: A
authors.lastname: Leecharoenkiat
authors.forename: Tirawat
authors.initials: T
authors.lastname: Wannatung
authors.forename: Pathrapol
authors.initials: P
authors.lastname: Lithanatudom
authors.forename: Saovaros
authors.initials: S
authors.lastname: Svasti
authors.forename: Suthat
authors.initials: S
authors.lastname: Fucharoen
authors.forename: Daranee
authors.initials: D
authors.lastname: Chokchaichamnankit
authors.forename: Chantragan
authors.initials: C
authors.lastname: Srisomsap
authors.forename: Duncan R
authors.initials: DR
authors.lastname: Smith
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western / Q000379:methods; D016022:Case-Control Studies; D002454:Cell Differentiation; D004789:Enzyme Activation; D004900:Erythroblasts / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D006019:Glycolysis; D006446:Hemoglobin E / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D010766:Phosphorylation; D040901:Proteomics; D017382:Reactive Oxygen Species / Q000032:analysis; D020298:U937 Cells; D017086:beta-Thalassemia / Q000097:blood / Q000503:physiopathology*
chemical_list: D017382:Reactive Oxygen Species; D006446:Hemoglobin E; D048049:Extracellular Signal-Regulated MAP Kinases