A mechanism of ineffective erythropoiesis in β-thalassemia/Hb E disease.
BACKGROUND
Cells respond to stress stimuli through a number of response pathways, of which one of the most important and well characterized is the unfolded protein response. Despite a large body of work which suggests that stress in erythroblasts may play a pivotal role in the pathogenesis of beta-thalassemia/Hb E disease, this pathway remains uninvestigated.


METHODS
Day 10 erythroblasts from normal controls and beta-thalassemia/Hb E patients were subjected to internal (treatment with tunicamycin) and external (serum and growth factor withdrawal) stress stimuli and the activation of the unfolded protein response pathway was investigated.


RESULTS
Normal erythroblasts responded to both internal and external stress by activating the unfolded protein response (UPR) pathway while in contrast, erythroblasts from beta-thalassemia/Hb E patients only showed activation of the unfolded protein response pathway in response to internal stress. This was reflected by a markedly increased induction of apoptosis in serum and growth factor deprived beta-thalassemia/Hb E erythroblasts as compared to control cells. Modulation of the levels of intracellular Ca(2+) in thalassemic erythroblasts restored UPR activation during serum deprivation and significantly reduced the level of serum deprivation induced apoptosis to control levels.


CONCLUSIONS
These results suggest the failure of thalassemic erythroblasts to cope with cellular stress caused by an impaired UPR function as a result of high Ca(2+) levels may exacerbate thalassemic cell death during erythropoiesis.
Lithanatudom
Pathrapol
P
Molecular Pathology Laboratory, Institute of Molecular Biosciences, Mahidol University, Salaya Campus, 25/25 Phuttamonthon Sai 4, Salaya, Nakon Pathom, Thailand 73170.
Leecharoenkiat
Amporn
A
Wannatung
Tirawat
T
Svasti
Saovaros
S
Fucharoen
Suthat
S
Smith
Duncan R
DR
D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D004900:Erythroblasts / Q000737:chemistry / Q000473:pathology*; D004920:Erythropoiesis / Q000502:physiology*; D005260:Female; D006446:Hemoglobin E / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D055550:Protein Stability; D058767:Protein Unfolding; D056811:Unfolded Protein Response / Q000235:genetics; D017086:beta-Thalassemia / Q000097:blood* / Q000235:genetics / Q000473:pathology*
D006446:Hemoglobin E