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Transcriptional alteration of DNA repair genes in Philadelphia chromosome negative myeloproliferative neoplasms.

Authors
  • Kirschner, Martin1
  • Bornemann, Anne2
  • Schubert, Claudia2
  • Gezer, Deniz2
  • Kricheldorf, Kim2
  • Isfort, Susanne2
  • Brümmendorf, Tim H2
  • Schemionek, Mirle2
  • Chatain, Nicolas2
  • Skorski, Tomasz3
  • Koschmieder, Steffen4
  • 1 Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany. [email protected] , (Germany)
  • 2 Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany. , (Germany)
  • 3 Sol Sherry Thrombosis Research Center and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
  • 4 Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany. [email protected] , (Germany)
Type
Published Article
Journal
Annals of Hematology
Publisher
Springer-Verlag
Publication Date
Dec 01, 2019
Volume
98
Issue
12
Pages
2703–2709
Identifiers
DOI: 10.1007/s00277-019-03836-2
PMID: 31748924
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Philadelphia negative (Ph-neg) myeloproliferative neoplasms (MPN) are a heterogenous group of clonal stem cell disorders. Approved treatment options include hydroxyurea, anagrelide, and ruxolitinib, which are not curative. The concept of synthetic lethality may become an additional therapeutic strategy in these diseases. In our study, we show that DNA repair is altered in classical Ph-neg MPN, as analyzed by gene expression analysis of 11 genes involved in the homologous recombination repair pathway (HRR), the non-homologous end-joining pathway (NHEJ), and the single-strand break repair pathway (SSB). Altogether, peripheral blood-derived cells from 57 patients with classical Ph-neg MPN and 13 healthy controls were analyzed. LIG3 as an essential part of the SSB was significantly lower expressed compared to controls in all three entities (essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF)). In addition, while genes of other DNA-repair pathways showed-possibly compensatory-increased expression in ET (HRR, NHEJ) and PV (NHEJ), MF samples displayed downregulation of all genes involved in NHEJ. With regard to the JAK2 mutational status (analyzed in ET and MF only), no upregulation of the HRR was detected. Though further studies are needed, based on these findings, we conclude that synthetic lethality may become a promising strategy in treating patients with Ph-neg MPN.

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