Chk1 Haploinsufficiency Results in Anemia and Defective Erythropoiesis

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.

Suppression of CHK1 by ETS Family Members Promotes DNA Damage Response Bypass and Tumorigenesis

“…To investigate this possibility, we generated a Pten +/− ;Chk1 +/− cohort of mice by crossing Pten +/− mice (38) with Chk1 +/− mice (39–41). Pten +/− ;Chk1 +/− male compound mutants behave and age in a similar manner to their Pten +/− littermates (Supplementary Fig.…”

Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

“…To achieve high resolution in separating stages (4) through (9) of terminal erythropoiesis, we assessed c-kit 33 and CD44 34 markers along side the widely used combination of CD71 and Ter119. 35 We used the membrane-permeant SYTO16 nucleic acid dye to assess enucleation 36 (Supplementary Figure S4A). LSD1-kd caused an expansion of PreMegE (1), PreCFU-E (2) and, most strikingly, phenotypic CFU-E (3) progenitors (Figures 4a and b).…”

Phase I dose-escalation study to examine the safety and tolerability of LY2603618, a checkpoint 1 kinase inhibitor, administered 1 day after pemetrexed 500 mg/m2 every 21 days in patients with cancer

“…Disruptions of Chk1 by inhibitors may lead to anemia [18] as reported from a Phase I study of UCN-01 where all patients developed Grade 3 hyperglycemia and the observed DLTs were hyphosphatemia and anemia [19]. However, the present study with the administration of LY2603618 in combination with pemetrexed showed neither anemia nor hyphosphatemia as DLT, but a Grade 3 diarrhea was observed in one patient at 105 mg/m 2 , a Grade 3 fatigue in one patient at 195 mg/m 2 , a Grade 4 allergic reaction/hypersensitivity was observed in one patient at 150 mg/m 2 , and Grade 4 thrombocytopenia in two patients at 195 mg/m 2 .…”