PARP-1 improves leukemia outcomes by inducing parthanatos during chemotherapy

Bruktawit Maru; Alessandra Messikommer; Linhui Huang; Katja Seipel; Olivia Kovecses; Peter J M Valk; Alexandre P A Theocharides; Francois E Mercier; Thomas Pabst; Maureen McKeague; Nathan W Luedtke

doi:10.1016/j.xcrm.2023.101191

PARP-1 improves leukemia outcomes by inducing parthanatos during chemotherapy

Cell Rep Med. 2023 Sep 19;4(9):101191. doi: 10.1016/j.xcrm.2023.101191. Epub 2023 Sep 7.

Affiliations

¹ Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
² Department of Chemistry, University of Zurich, Zurich, Switzerland.
³ Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland.
⁴ Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁵ Department of Medical Oncology and Hematology, University of Zurich and University Hospital Zurich, Zurich, Switzerland.
⁶ Division of Hematology and Experimental Medicine, Department of Medicine, McGill University, Montreal, QC, Canada.
⁷ Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada; Department of Chemistry, McGill University, Montreal, QC, Canada. Electronic address: maureen.mckeague@mcgill.ca.
⁸ Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada; Department of Chemistry, University of Zurich, Zurich, Switzerland; Department of Chemistry, McGill University, Montreal, QC, Canada. Electronic address: nathan.luedtke@mcgill.ca.

Abstract

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.

Keywords: NAD+ 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 test.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
Cell Line
Humans
Leukemia*
Leukocytes, Mononuclear
Poly(ADP-ribose) Polymerase Inhibitors* / pharmacology
Poly(ADP-ribose) Polymerase Inhibitors* / therapeutic use

Substances

Poly(ADP-ribose) Polymerase Inhibitors
PARP1 protein, human

Grants and funding

CIHR/Canada