Maru, BruktawitBruktawitMaruMessikommer, AlessandraAlessandraMessikommerHuang, LinhuiLinhuiHuangSeipel, KatjaKatjaSeipelKovecses, OliviaOliviaKovecsesValk, Peter J MPeter J MValkTheocharides, Alexandre P AAlexandre P ATheocharidesMercier, Francois EFrancois EMercierPabst, Thomas NiklausThomas NiklausPabstMcKeague, MaureenMaureenMcKeagueLuedtke, Nathan WNathan WLuedtke2024-10-252024-10-252023-09-19https://boris-portal.unibe.ch/handle/20.500.12422/169886Previous chemotherapy research has focused almost exclusively on apoptosis. Here, a standard frontline drug combination of cytarabine and idarubicin induces distinct features of caspase-independent, poly(ADP-ribose) polymerase 1 (PARP-1)-mediated programmed cell death "parthanatos" in acute myeloid leukemia (AML) cell lines (n = 3/10 tested), peripheral blood mononuclear cells from healthy human donors (n = 10/10 tested), and primary cell samples from patients with AML (n = 18/39 tested, French-American-British subtypes M4 and M5). A 3-fold improvement in survival rates is observed in the parthanatos-positive versus -negative patient groups (hazard ratio [HR] = 0.28-0.37, p = 0.002-0.046). Manipulation of PARP-1 activity in parthanatos-competent cells reveals higher drug sensitivity in cells that have basal PARP-1 levels as compared with those subjected to PARP-1 overexpression or suppression. The same trends are observed in RNA expression databases and support the conclusion that PARP-1 can have optimal levels for favorable chemotherapeutic responses.enNAD+ ADP-ribosyltransferase 1 PAR PARP-1 acute myelomonocytic and monocytic leukemia apoptosis cancer biology caspase-independent programmed cell death nucleoside analog poly(ADP-ribose) precision medicine prognostic blood test600 - Technology::610 - Medicine & healtharticle10.48350/1862003768365010.1016/j.xcrm.2023.101191