Increased erythropoiesis of beta-thalassaemia/Hb E proerythroblasts is mediated by high basal levels of ERK1/2 activation.
Beta-thalassaemia is one of the most common inherited anaemias, arising from a partial or complete loss of beta-globin chain synthesis. In severe cases, marked bone marrow erythroid hyperplasia, believed to result from erythropoietin (EPO)-mediated feedback from the anaemic condition is common, however, as yet, no study has investigated EPO-mediated signal transduction in thalassaemic erythroid cells. Using proerythroblasts generated from peripheral blood circulating CD34+ haematopoietic progenitor cells, the activation of the mitogen-activated protein kinase/extracellular signal-regulated kinases (MAPK/ERKs) pathway was examined under conditions of steady state growth, cytokine deprivation and post-EPO stimulation. Levels of cellular cyclic adenosine monophosphate (cAMP) and Ca2+ were determined as was the degree of erythroid expansion. A significantly higher basal level of phosphorylation of ERK1/2 was observed in beta-thalassaemia/Hb E proerythroblasts as compared to normal controls, which was coupled with significantly higher levels of both cAMP and Ca2+. Modulation of either cAMP or Ca2+ or direct inhibition of MAPK/ERK kinase (MEK) reduced basal levels of ERK1/2 phosphorylation, as well as significantly reducing the level of erythroid expansion. These results suggest that, in contrast to current models, hyper proliferation of beta-thalassaemia/Hb E proerythroblasts is an intrinsic process driven by higher basal levels of ERK1/2 phosphorylation resulting from deregulation of levels of cAMP and Ca2+.
Wannatung
Tirawat
T
Molecular Pathology Laboratory, Institute of Molecular Biosciences, Mahidol University, Nakorn Pathom, Thailand.
Lithanatudom
Pathrapol
P
Leecharoenkiat
Amporn
A
Svasti
Saovaros
S
Fucharoen
Suthat
S
Smith
Duncan R
DR
D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western / Q000379:methods; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism; D004789:Enzyme Activation; D004900:Erythroblasts / Q000502:physiology*; D004920:Erythropoiesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D017086:beta-Thalassemia / Q000097:blood*
D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium