Abstract
Erythroidl eukemia 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 erythro leukemia 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
Highlights
TNF-related apoptosis inducing ligand (TRAIL/APO2L) is a death ligand member of the TNF cytokine super family that interacts with five different receptors, two of which can initiate apoptosis, whereas the other three are regulatory or decoy receptors (DcR1, DcR2 and osteoprotegerin (OPG))
Binding of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) to DR4 or DR5 results in receptor activation followed by sequential recruitment of the adaptor protein Fas-associated death domain (FADD) and pro-caspase-8, forming the death-inducing signalling complex (DISC)
We found that TRAIL sensitivity is linked to normal cell cycle progression as cells in early G1 or G2/M phase isolated by elutriation displayed higher TRAIL-sensitivity, which correlated with a cell cycledependent, oscillating expression of the anti-apoptotic protein cFLIP
Summary
TNF-related apoptosis inducing ligand (TRAIL/APO2L) is a death ligand member of the TNF cytokine super family that interacts with five different receptors, two of which can initiate apoptosis (death receptors DR4 and DR5), whereas the other three are regulatory or decoy receptors (DcR1, DcR2 and osteoprotegerin (OPG)). Binding of TRAIL to DR4 or DR5 results in receptor activation followed by sequential recruitment of the adaptor protein Fas-associated death domain (FADD) and pro-caspase-8, forming the death-inducing signalling complex (DISC). At the DISC, pro-caspase-8 is auto activated and initiates a caspase cascade resulting in dismantling of cellular components and consequent cell death [1]. Acute erythroidleukemia (AEL) is a rare form of acute myeloid leukemia (AML) with generally poor prognosis. AEL is a heterogeneous disease often driven by highly undifferentiated myelogenic progenitor cells characterised by genetic instability and poor prognosis with the erythroidleukemia (pEL) subtype having a patient median survival of 3 ± 3.6 months [3]
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