title: Poly (ADP-Ribose) Polymerase Inhibitor Hypersensitivity in Aggressive Myeloproliferative Neoplasms.
abstract: DNA repair defects have been previously reported in myeloproliferative neoplasms (MPN). Inhibitors of PARP have shown activity in solid tumors with defects in homologous recombination (HR). This study was performed to assess MPN sensitivity to PARP inhibitors ex vivo
  
  
  
  HR pathway integrity in circulating myeloid cells was evaluated by assessing the formation of RAD51 foci after treatment with ionizing radiation or PARP inhibitors. Sensitivity of MPN erythroid and myeloid progenitors to PARP inhibitors was evaluated using colony formation assays.
  
  
  
  Six of 14 MPN primary samples had reduced formation of RAD51 foci after exposure to ionizing radiation, suggesting impaired HR. This phenotype was not associated with a specific MPN subtype, JAK2 mutation status, or karyotype. MPN samples showed increased sensitivity to the PARP inhibitors veliparib and olaparib compared with normal myeloid progenitors. This hypersensitivity, which was most pronounced in samples deficient in DNA damage-induced RAD51 foci, was observed predominantly in samples from patients with diagnoses of chronic myelogenous leukemia, chronic myelomonocytic leukemia, or unspecified myelodysplastic/MPN overlap syndromes.
  
  
  
  Like other neoplasms with HR defects, MPNs exhibit PARP inhibitor hypersensitivity compared with normal marrow. These results suggest that further preclinical and possibly clinical study of PARP inhibitors in MPNs is warranted. Clin Cancer Res; 22(15); 3894-902. ©2016 AACR.
authors.affiliation: Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland. Kpratz1@jhmi.edu.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Pratz
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Koh
authors.affiliation: Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Anand G
authors.initials: AG
authors.lastname: Patel
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Flatten
authors.affiliation: Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland.
authors.forename: Weijie
authors.initials: W
authors.lastname: Poh
authors.affiliation: Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.affiliation: Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland.
authors.forename: Robert
authors.initials: R
authors.lastname: Dilley
authors.affiliation: Department of Obstetrics & Gynecology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Harrell
authors.affiliation: Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland.
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.affiliation: Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland.
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.affiliation: Department of Obstetrics & Gynecology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Swisher
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDevitt
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota. Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D019313:BRCA1 Protein / Q000235:genetics; D001562:Benzimidazoles / Q000009:adverse effects / Q000494:pharmacology; D004249:DNA Damage; D019175:DNA Methylation; D004260:DNA Repair; D004342:Drug Hypersensitivity / Q000209:etiology*; D004361:Drug Tolerance / Q000235:genetics; D023281:Genomics / Q000379:methods; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000150:complications* / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D051135:Rad51 Recombinase