We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
A role for reactive oxygen species in JAK2<sup>V617F</sup> myeloproliferative neoplasm progression.
- Authors
Marty, C; Lacout, C; Droin, N; Le Couédic, J-P; Ribrag, V; Solary, E; Vainchenker, W; Villeval, J-L; Plo, I
- 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.
- Publication
Leukemia (08876924), 2013, Vol 27, Issue 11, p2187
- ISSN
0887-6924
- Publication type
Academic Journal
- DOI
10.1038/leu.2013.102