Chk1 Haploinsufficiency Results in Anemia and Defective Erythropoiesis

Erythropoiesis is a highly regulated and well-characterized developmental process responsible for providing the oxygen transport system of the body. However, besides erythropoietin’s role, 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. Chk1 expression in the hematopoietic system has been demonstrated to be restricted to T-cells, erythroid cells and the hematopoietic stem cell. Interestingly, a lack of Chk1 has recently been shown to disrupt T-cell differentiation (Zaugg et al. PNAS 2007) Here, we show that haploinsufficiency of Chk1 leads to a 30% increase in the incidence of anemia in mice. Furthermore, the anemic Chk1 +/− mice exhibit distorted spleen and bone marrow architecture, and an increase in erythroid progenitors (MEP, stages I, and II). In young non-anemic Chk1 +/− mice, a decrease in enucleated cells of the erythroid lineage is observed, suggesting a role for Chk1 in proper erythroid enucleation. In addition, a decrease in Chk1 RNA has been observed in patients with refractory anemia with excess blasts (Pellagatti et al. Blood, 2006), further supporting an important role for Chk1 status in clinical anemia. Finally, Chk1 has recently been show to affect the regulation of Fancd2, one of the gene’s responsible for Fanconi anemia. These results indicate Chk1 plays a part in maintaining the balance between erythroid progenitors and the enucleated erythroid cells during differentiation.