Transcriptional alteration of DNA repair genes in Philadelphia chromosome negative myeloproliferative neoplasms
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.
KeywordsDNA repair Gene expression Myeloproliferative neoplasms
We thank Kristina Feldberg for the excellent technical assistance.
The data presented in this publication will be part of the doctoral thesis of Anne Bornemann (co-author) which will be published in future.
MK: performed parts of the experiments, analyzed and interpreted the data, and wrote the manuscript. AB: performed parts of the experiments, analyzed the data, and revised the manuscript. CS: performed parts of the experiments, analyzed the data, and revised the manuscript. DG: Collected the clinical data and revised the manuscript. KK: Collected the clinical data and revised the manuscript. SI: interpreted the data and revised the manuscript. THB: analyzed and interpreted the data and revised the manuscript. MS: analyzed and interpreted the data and revised the manuscript. NC: analyzed and interpreted the data and revised the manuscript. TS: analyzed and interpreted the data and revised the manuscript. SK: conceived and planned the study design, interpreted the data, and revised the manuscript.
Steffen Koschmieder was supported by a grant of the German research Foundation (DFG KO 2155/6-1).
Compliance with ethical standards
Conflict of interest
THB: Consultancy: Novartis, Pfizer, Janssen, Merck; research funding: Novartis, Pfizer. SK: reports funding from Novartis, Bristol-Myers Squibb and Janssen, as well as consultancy, honoraria, and travel support from Novartis, Incyte, Ariad, Bristol-Myers Squibb, AOP, CTI, Pfizer, Celgene, and Shire. The other authors declare that they have no conflict of interest.
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