G2/M Arrest Sensitises Erythroid Leukemia Cells to TRAIL-induced Apoptosis

Abstract

Erythroid leukemia is a heterogeneous disease with very poor prognosis. It may arise de novo, secondary to myelodysplastic syndrome, blast crisis phase of chronic myeloid leukemia, or after cytotoxic therapy of acute myeloid leukemia. The current mainstream treatment of erythroleukemia is cytarabine and anthracyclin-based chemotherapy or bone marrow transplantation. In the current study we found that cytarabine or inhibition of the DNA-damage-activated protein kinase, ATM, induce G2/M arrest and sensitised K562 erythroleukemia cells to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Arresting cells in G2/M with microtubule-disrupting drugs also enhanced TRAIL-sensitivity. Synchronisation or separation of the leukemia cells in different stages of the cell cycle by elutriation confirmed that the cells in G1 and G2/M were sensitive to TRAIL. Interestingly, this sensitivity was associated with cell cycle-dependent oscillation of cFLIP expression. In summary, we found that combination of cytostatic drugs with TRAIL can be an effective treatment for erythroid leukemia.