Study of the regulation of the G2/M checkpoint in acute myeloid leukemia cell lines Free

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Acute myelocytic leukemia (AML) cells exposed to genotoxic agents arrest their cell cycle at the G2/M checkpoint and are naturally chemoresistant. To gain insight in the understanding of this resistance, we compared the ability of immature CD34+ versus mature CD34- AML cell lines (KG1a and U937 respectively) to bypass a DNA damage cell cycle checkpoint in G2. Here, we report evidence for a more stringent control of G2/M checkpoint in KG1a than in U937 cells. We show that in both cell types the CDC25B phosphatase and the PLK1 kinase participate to the G2/M checkpoint recovery. We also show that inhibition of CHK1 by UCN-01 in immature KG1a cells allows checkpoint exit and sensibilisation to genotoxic agent. Finally, UCN-01 potentialises genotoxic-induced inhibition of plating efficiency of AML blasts from patients.

Together our results demonstrate that checkpoint stringency varies during maturation process and indicate that targeting checkpoint mechanisms might represent an attractive therapeutic opportunity for chemoresistant immature AML.