Stress-induced hematopoietic failure in the absence of immediate early response gene X-1 (IEX-1, IER3).
Expression of the immediate early response gene X-1 (IEX-1, IER3) is diminished significantly in hematopoietic stem cells in a subgroup of patients with early stage myelodysplastic syndromes, but it is not clear whether the deregulation contributes to the disease. The current study demonstrates increased apoptosis and a concomitant decrease in the number of hematopoietic stem cells lacking this early response gene. Null mutation of the gene also impeded platelet differentiation and shortened a lifespan of red blood cells. When bone marrow cells deficient in the gene were transplanted into wild-type mice, the deficient stem cells produced significantly fewer circulating platelets and red blood cells, despite their enhanced repopulation capability. Moreover, after exposure to a non-myeloablative dose of radiation, absence of the gene predisposed to thrombocytopenia, a significant decline in red blood cells, and dysplastic bone marrow morphology, typical characteristics of myelodysplastic syndromes. These findings highlight a previously unappreciated role for this early response gene in multiple differentiation steps within hematopoiesis, including thrombopoiesis, erythropoiesis and in the regulation of hematopoietic stem cell quiescence. The deficient mice offer a novel model for studying the initiation and progression of myelodysplastic syndromes as well as strategies to prevent this disorder.
mwu2@partners.org.
Haley
H
Ramsey
Qi
Q
Zhang
Diane E
DE
Brown
David P
DP
Steensma
Charles P
CP
Lin
Mei X
MX
Wu
D064591:Allografts; D000818:Animals; D017209:Apoptosis; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013312:Stress, Physiological
C518820:IEX-1 protein, mouse; D017874:Immediate-Early Proteins