Abstract
Although other mutations may predate the acquisition of the JAK2V617F mutation, the latter is sufficient to drive the disease phenotype observed in BCR-ABL-negative myeloproliferative neoplasms (MPNs). One of the consequences of JAK2V617F is genetic instability that could explain JAK2V617F-mediated MPN progression and heterogeneity. Here, we show that JAK2V617F induces the accumulation of reactive oxygen species (ROS) in the hematopoietic stem cell compartment of a knock-in (KI) mouse model and in patients with JAK2V617F MPNs. JAK2V617F-dependent ROS elevation was partly mediated by an AKT-induced decrease in catalase expression and was accompanied by an increased number of 8-oxo-guanines and DNA double-strand breaks (DSBs). Moreover, there was evidence for a mitotic recombination event in mice resulting in loss of heterozygosity of Jak2V617F. Mice engrafted with 30% of Jak2V617F KI bone marrow (BM) cells developed a polycythemia vera-like disorder. Treatment with the anti-oxidant N-acetylcysteine (NAC) substantially restored blood parameters and reduced damages to DNA. Furthermore, NAC induced a marked decrease in splenomegaly with reduction in the frequency of the Jak2V617F-positive hematopoietic progenitors in BM and spleen. Altogether, overproduction of ROS is a mediator of JAK2V617F-induced DNA damages that promote disease progression. Targeting ROS accumulation might prevent the development of JAK2V617F MPNs.
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Acknowledgements
We thank the animal facility of Institut Gustave Roussy and Olivia Bawa for histopathological analysis. We thank P Rameau and Y Lécluse for cell sorting and flow cytometry analysis (IRCIV, Institut Gustave Roussy, Villejuif, France). This work was supported by grants from La Ligue Nationale Contre le Cancer ‘Equipe labellisée 2007 and 2012’, ARC (projet libre 2012), ANR (Thrombocytose), ANR Blanc (Epigénome) and INSERM. CM was funded by a post-doctoral fellowship from the Ile-de-France Cancéropôle and INCa and then supported by a labex GR-Ex fellowship. Labex GR-Ex (IP, VW) is funded by the program ‘Investissements d’avenir’.
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Marty, C., Lacout, C., Droin, N. et al. A role for reactive oxygen species in JAK2V617F myeloproliferative neoplasm progression. Leukemia 27, 2187–2195 (2013). https://doi.org/10.1038/leu.2013.102
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DOI: https://doi.org/10.1038/leu.2013.102
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