Abstract
BackgroundErythropoiesis 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.Methodology/Principal FindingsHere, 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/SignificanceClinical 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.
Highlights
In a recent study, we used microarrays to examine gene expression differences in several hematopoietic cell types and found the cell cycle regulator Checkpoint Kinase 1 homolog (Chk1) to be highly expressed in hematopoietic stem cells, T-cells, and erythroid progenitors as compared to the other cell types (Figure 1A) [1]
A marked increase in DNA damage foci was observed in both proliferating and differentiating Chk1+/2 erythroid progenitors during erythropoiesis, whereas wild type (WT) erythroid cells did not display DNA damage foci. These results demonstrate that haploinsufficiency of Chk1 in the proliferating erythroblasts resulted in the accumulation of DNA damage, which possibly caused a block or miscoordinated erythroid differentiation and fewer mature red blood cells
The results presented here show that Chk1 plays a role in red blood cell formation
Summary
We used microarrays to examine gene expression differences in several hematopoietic cell types and found the cell cycle regulator Checkpoint Kinase 1 homolog (Chk1) to be highly expressed in hematopoietic stem cells, T-cells, and erythroid progenitors as compared to the other cell types (Figure 1A) [1]. Erythroid cell development is a highly regulated multi-stage process resulting in the production of red blood cells (RBCs). Erythropoietin is the best understood factor promoting erythropoiesis, and is already used in the clinical setting [3]. Until recently, the latter phases of erythroid development, i.e. the processes responsible for enucleation and the final stages of differentiation were poorly, if at all, characterized [4,5,6,7]. 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
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