A role for reactive oxygen species in [JAK2.sup.V617F] myeloproliferative neoplasm progression

Although other mutations may predate the acquisition of the [JAK2.sup.V617F] mutation, the latter is sufficient to drive the disease phenotype observed in BCR-ABL-negative myeloproliferative neoplasms (MPNs). One of the consequences of [JAK2.sup.V617F] is genetic instability that could explain [JAK2.sup.V617F]-mediated MPN progression and heterogeneity. Here, we show that [JAK2.sup.V617F] 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 [JAK2.sup.V617F] MPNs. [JAK2.sup.V617F]-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 [Jak.sup.2V617F]. Mice engrafted with 30% of [Jak2.sup.V617F] 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 [Jak2.sup.V617F]-positive hematopoietic progenitors in BM and spleen. Altogether, overproduction of ROS is a mediator of [JAK2.sup.V617F]-induced DNA damages that promote disease progression. Targeting ROS accumulation might prevent the development of [JAK2.sup.V617F] MPNs. Leukemia (2013) 27, 2187-2195; doi: 10.1038/leu.2013.102 Keywords: myeloproliferative neoplasms;[JAK2.sup.V617F]; reactive oxygen species; N-acetylcysteine; DNA damages; knock- in mouse model