PARP-1 improves leukemia outcomes by inducing parthanatos during chemotherapy.

Maru, Bruktawit; Messikommer, Alessandra; Huang, Linhui; Seipel, Katja; Kovecses, Olivia; Valk, Peter J M; Theocharides, Alexandre P A; Mercier, Francois E; Pabst, Thomas; McKeague, Maureen; Luedtke, Nathan W (2023). PARP-1 improves leukemia outcomes by inducing parthanatos during chemotherapy. Cell reports. Medicine, 4(9), p. 101191. Elsevier 10.1016/j.xcrm.2023.101191

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Previous 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.

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