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Bone marrow PARP1 mRNA levels predict response to treatment with 5-azacytidine in patients with myelodysplastic syndrome

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Abstract

Poly (ADP-ribose) polymerase 1 (PARP1) is a nuclear enzyme that participates in the DNA repair of malignant cells, with various consequences on their survival. We have recently shown that PARP1 mRNA levels in the bone marrow of patients with myelodysplastic syndrome (MDS) are correlated to prognosis. To evaluate PARP1 as a biomarker of response to 5-azacytidine in patients with MDS, we measured PARP1 mRNA levels by a quantitative real-time PCR in diagnostic bone marrow samples of 77 patients with MDS treated with 5-azacytidine. Patients with higher PARP1 mRNA levels had a better response to 5-azacytidine per the IWG criteria (p = 0.006) and a longer median survival after 5-azacytidine initiation (p = 0.033). Multivariate analysis revealed that PARP1 mRNA level was the only factor affecting response to treatment and survival after treatment with 5-azacytidine. A next-generation sequencing for 40 genes of interest in MDS and quantification of the methylation levels of the PARP1 promoter were also carried out in a subset of samples (16 and 18 samples respectively). It is the first time that a single, easily measurable biomarker shows a clear correlation with response to treatment and survival in a patient population consisting of previously untreated patients with MDS homogeneously treated with 5-azacytidine. The fact that PARP1 is also a treatment target in several malignancies underscores the importance of our finding for the potential use of PARP1 inhibitors in MDS.

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Acknowledgments

We would like to thank Mr. George Kyriakakis for his valuable help in data collection and digitization, Mrs. Angeliki Stefanou for the delicate sample-handling and storage, Mrs. Evita Alexopoulos for copy-editing the final manuscript, and Professor Demosthenes Panagiotakos for his valuable contribution in the statistical analysis of the results.

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Authors and Affiliations

  1. Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 17 Agiou Thoma street, 11527, Athens, Greece

    Panagiotis T. Diamantopoulos, Christina-Nefeli Kontandreopoulou, Theodoros Vassilakopoulos, Marina Siakantaris, Maria Angelopoulou & Nora-Athina Viniou

  2. Department of Internal Medicine, University Hospital of Patras, Rio, Greece

    Argiris Symeonidis, Eleni Solomou, Alexandra Kourakli & Georgia Christopoulou

  3. Department of Hematology, University Hospital of Alexandroupolis, Alexandroupoli, Greece

    Ioannis Kotsianidis

  4. Haematology Division, Second Department of Internal Medicine, Attikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece

    Vassiliki Pappa & Sotirios Papageorgiou

  5. Department of Clinical Hematology, ‘G. Gennimatas’ District General Hospital, Athens, Greece

    Athanasios Galanopoulos

  6. First Department of Propedeutic Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece

    Maria Dimou, Marie-Christine Kyrtsonis, Maria Roumelioti & Panayiotis Panayiotidis

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  1. Panagiotis T. Diamantopoulos
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  2. Christina-Nefeli Kontandreopoulou
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On behalf of the Hellenic MDS Study Group

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Correspondence to Panagiotis T. Diamantopoulos.

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Informed consent was obtained in accordance with the Declaration of Helsinki. The study was approved by the Institutional Ethics Committee.

Conflict of interest

Argiris Symeonidis, Alexandra Kourakli, and Nora-Athina Viniou report investigational grants and personal fees for presentations and advisory roles from Celgene/Genesis Pharma. Ioannis Kotsianidis, Vassiliki Pappa, Athanasios Galanopoulos, Theodoros Vassilakopoulos, Maria Angelopoulou, Sotirios Papageorgiou, and Panayiotis Panayiotidis report personal fees for honoraria and advisory roles from Celgene/Genesis Pharma. Maria Dimou reports personal fees for advisory roles from Celgene/Genesis Pharma. The remaining authors declare that they have no conflict of interest.

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Diamantopoulos, P.T., Kontandreopoulou, CN., Symeonidis, A. et al. Bone marrow PARP1 mRNA levels predict response to treatment with 5-azacytidine in patients with myelodysplastic syndrome. Ann Hematol 98, 1383–1392 (2019). https://doi.org/10.1007/s00277-019-03650-w

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