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Cancer Prognosis According to Parthanatos Features

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Cancer Prognosis According to Parthanatos Features bioRxiv preprint doi: https://doi.org/10.1101/2021.05.24.445484; this version posted May 25, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Cancer Prognosis According to Parthanatos Features Alessandra Messikommer,1 Bruktawit Maru,2 Katja Seipel,3 Peter J. M. Valk,4 Alexandre P.A. Theocharides,5 Thomas Pabst,3 Maureen McKeague,2,6* Nathan W. Luedtke1,2,6* 1 Department of Chemistry, University of Zurich, CH-8057 Zurich, Switzerland 2 Department of Pharmacology and Therapeutics, McGill University, Montreal, H3G 1Y6, Canada 3 Department of Medical Oncology, University Hospital Inselspital, CH-3010 Bern, Switzerland 4 Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, Netherlands 5 Department of Medical Oncology and Hematology, University of Zurich and University Hospital Zurich, Zurich, Switzerland 6 Department of Chemistry, McGill University, Montreal, H3A 0B8, Canada * Address all correspondence to: Nathan W. Luedtke, McGill University, Montreal, H3A 0B8, Canada. E-mail: [email protected] or to Maureen McKeague, McGill University, Montreal, H3G 1Y6, Canada. E-mail: [email protected] In Brief: Messikommer and co-workers report that PARP-1-mediated programmed cell death is associated with successful, front-line treatment of acute myeloid leukemia (AML). Highlights: The first-line cancer drug cytarabine (ara-C) induces parthanatos or apoptosis, depending on the specific AML cell line being treated. OCI-AML3 cells undergo parthanatos or apoptosis, depending on the specific drug being added. The presence of two parthanatos features in primary cancer cells from AML patients (n = 18 of 39 tested) having French-American-British (FAB) subclassifications M4 or M5 is associated with four-fold improved survival (HR = 0.23, p = 0.01) following curative chemotherapy with ara-C and an anthracycline. The poly [ADP-ribose] polymerase (PARP) inhibitor Olaparib exhibits antagonistic activities against ara-C and idarubicin in primary blood monocytes from healthy donors as well as primary cancer isolates from ~50% of AML patients. Near-median expression of PARP1 mRNA is associated with a 50% increase in survival time (HR = 0.66, p = 0.01) of AML patients following chemotherapy with ara-C and idarubicin. 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.24.445484; this version posted May 25, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. GRAPHICAL ABSTRACT SUMMARY For nearly 50 years, translational research studies aimed at improving chemotherapy-induced killing of cancer cells have focused on the induction of apoptosis. Here we show that a PARP-1-mediated programmed cell death mechanism “parthanatos” is associated with the successful, front-line treatment of a common cancer. Peripheral blood mononuclear cells (PBMCs) from healthy human donors (10 of 10 tested), as well as primary cancer cells from approximately 50% of acute myeloid leukemia (AML) patients (n = 18 of 39 tested, French-American-British (FAB) subtypes M4 and M5) exhibited two distinctive features of parthanatos upon treatment with a front-line drug combination of cytarabine and an anthracycline. Statistically significant improvements in survival rates were observed in the parthanatos positive versus parthanatos negative AML patient groups (HR = 0.22 – 0.38, p = 0.002 – 0.05). Near-median expression of PARP1 mRNA was associated with a 50% longer survival time (HR = 0.66, p = 0.01), and the poly [ADP-ribose] polymerase (PARP) inhibitor Olaparib exhibited antagonistic activities against ara-C and idarubicin in primary blood monocytes from healthy donors as well as primary cancer isolates from ~50% of AML patients. Together these results suggest that PARP activity is a prognostic biomarker for AML subtypes M4 and M5 and support the relevance of parthanatos in curative chemotherapy of AML. 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.24.445484; this version posted May 25, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. INTRODUCTION Acute myeloid leukemia (AML) is the most common and malicious form of leukemia in adults, with an approximate 30% five-year overall survival rate for patients receiving curative therapies (Costa et al., 2017). The histology-based French-American-British (FAB) subclassification system helped identify acute promyelocytic leukemia (APL, subtype M3) as a separate and highly curable subtype of AML, but it only accounts for ~10% of AML patients (Cicconi and Lo-Coco, 2016). The remaining 90% of AML patients are classified by a prognosis-based system established by the World Health Organization and European LeukemiaNet (ELN) that divides patients into three risk groups (favorable, intermediate, and adverse) based on the presence of cytogenetic and mutational biomarkers. Despite a growing number of new auxiliary and palliative AML therapies becoming available (Kopmar and Estey, 2019), the frontline, curative treatment of eligible patients from all three risk groups commences with a 7-day infusion of cytarabine (ara-C) that is typically augmented with an anthracycline for three days known as “7+3” induction chemotherapy (Estey, 2018). Even after 50 years of widespread clinical use, the mechanisms responsible for ara-C’s selective killing of white blood cells remain poorly understood. Previous studies have focused on metabolic incorporation of ara-C into DNA and downstream apoptosis (Cassier et al., 2017; Deng et al., 2017; Harrison et al., 2016; Schneider et al., 2017; Vincelette and Yun, 2014). However, recent reports suggest that ara-C incorporation into primer RNA is responsible for its therapeutic efficacy (Messikommer et al., 2020; Triemer et al., 2018), and active killing of AML primary isolates by ara-C can be a caspase-independent process (Carter et al., 2003). DNA damage and stimulation of apoptosis have been focal areas of chemotherapeutic drug development for leukemia and other cancers for nearly 50 years (Carneiro and El-Deiry, 2020). Cells that lose tumor suppressor activities by p53 mutation (Kandoth et al., 2013) can gain resistance against standard chemotherapeutic drugs by dysregulation of apoptosis (Mohammad et al., 2015; Wong et al., 2015). Targeted therapies that re-sensitize cells towards apoptosis such as B-cell leukemia/lymphoma-2 (Bcl-2) family inhibitors (Jonas and Pollyea, 2019) as well as p53 “reactivators”(Pan et al., 2017) can overcome apoptosis resistance. However, primary AML cells treated with ara-C can undergo caspase-independent programmed cell death (Carter et al., 2003), and caspase-3 activation failed to predict ara-C and anthracycline drug sensitivity of primary AML isolates from 42 patients (Staib et al., 2005). A potential explanation for these observations is that healthy and diseased white blood cells may undergo non-apoptotic forms of programmed cell death during chemotherapy such as autophagic cell death (Auberger and Puissant, 2017; Kajiume and Kobayashi, 2018), necroptosis (Huang et al., 2018; Mezzatesta and Bornhauser, 2019), pyroptosis (Xia et al., 2019), and/or parthanatos (Cloux et al., 2019). Parthanatos has been recognized as a distinct mode of programmed cell death by the Nomenclature Committee on Cell Death since 2012 (Galluzzi et al., 2018; Galluzzi et al., 2012). Poly [ADP-ribose] polymerase 1 (PARP-1) is the primary orchestrator of parthanatos (Wang et al., 2011). Abnormal expression of PARP1 is associated with poor clinical outcomes in breast cancer (Rojo et al., 2012) and AML (Li et al., 2018; Pashaiefar et al., 2018; Wang et al., 2015). PARP-1-mediated cell death has been reported in white blood cells treated with reactive oxygen species (Cloux et al., 2019; Robinson et al., 2019). Parthanatos proceeds via activation of PARP-1 by chromatin stress (Prokhorova et al., 2020), accumulation of poly-ADP ribose (PAR), and translocation of apoptosis-inducing factor (AIF) from the mitochondria into the nucleus where it activates nuclease macrophage migration inhibitory factor (MIF) (Andrabi et al., 2008; David et al., 2009; Wang et al., 2016). Once activated, 3 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.24.445484; this version posted May 25, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. MIF selectively cleaves single-stranded DNA to generate very large chromatin fragments of ~50 kb (Fatokun et al., 2014; Wang et al., 2016). In contrast to both necroptosis (Mezzatesta and Bornhauser, 2019) and pyroptosis (Xia et al., 2019), parthanatos proceeds with retention of plasma membrane integrity and flipping of phosphatidylserine onto the outer surface of the cell (Leong et al., 2010; Zuber et al., 2009). As such, parthanatos cannot be distinguished from apoptosis using standard assay kits, for example by using only annexin V and propidium iodide staining (Fatokun et al., 2014; Wang et al., 2009). Additional experiments are required to distinguish between parthanatos and apoptosis, such as chromatin fragment analysis (Huang et al., 1995; Wang et al., 2009) or evaluating the impact of PARP-1 inhibition on drug sensitivity (Cloux et al., 2019). Here, we report that PARP-1-mediated
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