Chk1 haploinsufficiency results in anemia and defective erythropoiesis.
BACKGROUND
Erythropoiesis is a highly regulated and well-characterized developmental process responsible for providing the oxygen transport system of the body. However, few of the mechanisms involved in this process have been elucidated. Checkpoint Kinase 1 (Chk1) is best known for its role in the cell cycle and DNA damage pathways, and it has been shown to play a part in several pathways which when disrupted can lead to anemia.


RESULTS
Here, we show that haploinsufficiency of Chk1 results in 30% of mice developing anemia within the first year of life. The anemic Chk1+/- mice exhibit distorted spleen and bone marrow architecture, and abnormal erythroid progenitors. Furthermore, Chk1+/- erythroid progenitors exhibit an increase in spontaneous DNA damage foci and improper contractile actin ring formation resulting in aberrant enucleation during erythropoiesis. A decrease in Chk1 RNA has also been observed in patients with refractory anemia with excess blasts, further supporting a role for Chk1 in clinical anemia.


CONCLUSIONS
Clinical trials of Chk1 inhibitors are currently underway to treat cancer, and thus it will be important to track the effects of these drugs on red blood cell development over an extended period. Our results support a role for Chk1 in maintaining the balance between erythroid progenitors and enucleated erythroid cells during differentiation. We show disruptions in Chk1 levels can lead to anemia.
Boles
Nathan C
NC
Interdepartmental Program in Cell and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
Peddibhotla
Sirisha
S
Chen
Alice J
AJ
Goodell
Margaret A
MA
Rosen
Jeffrey M
JM
D000740:Anemia / Q000235:genetics*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D000071877:Checkpoint Kinase 1; D004920:Erythropoiesis / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D051379:Mice; D011494:Protein Kinases / Q000235:genetics*
D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse