A role for reactive oxygen species in JAK2V617F myeloproliferative neoplasm progression

Abstract

Although other mutations may predate the acquisition of the JAK2(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(V617F) is genetic instability that could explain JAK2(V617F)-mediated MPN progression and heterogeneity. Here, we show that JAK2(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(V617F) MPNs. JAK2(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 Jak2(V617F). Mice engrafted with 30% of Jak2(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(V617F)-positive hematopoietic progenitors in BM and spleen. Altogether, overproduction of ROS is a mediator of JAK2(V617F)-induced DNA damages that promote disease progression. Targeting ROS accumulation might prevent the development of JAK2(V617F) MPNs.

NOX-driven ROS formation in cell transformation of FLT3-ITD-positive AML

“…elevated levels of DNA damage [40]. In neutrophils from JAK2 V617F positive patients, an increased phosphorylation of the NOX2 subunit p47 phox on Ser345 has been observed, suggesting a contribution of NOX2 activation to elevated levels of ROS in MDS [41].…”

“…The mutation is present in approximately 6% of myelodysplastic syndromes (MDS) and 50% of myeloproliferative neoplasms (MPNs) [38]. Signaling of the JAK2 V617F oncoprotein results in constitutive activation of downstream pro-survival signaling, including activation of STAT5, PI3K/AKT and RAF/MEK/ERK, and in turn the formation of ROS [39,40]. The increase in ROS is concurrent with M A N U S C R I P T…”

FOXO3 Transcription Factor Is Essential for Protecting Hematopoietic Stem and Progenitor Cells from Oxidative DNA Damage

“…ROS are generated both endogenously by cell metabolism or expression of oncoproteins and exogenously by ionizing radiation and genotoxic drugs (1,5,6). ROS induce single and double strand DNA breaks as well as various species of oxidized nucleotides and are implicated in the pathophysiology of hematological malignancies (7). Thus, modulations of ROS may be used therapeutically (7,8).…”

“…ROS induce single and double strand DNA breaks as well as various species of oxidized nucleotides and are implicated in the pathophysiology of hematological malignancies (7). Thus, modulations of ROS may be used therapeutically (7,8). Cells, with distinct kinetics, constantly repair oxidative damage using mainly the base excision repair (BER) pathway (9).…”

Estimate of JAK 2 V617F Mutation and Activity of Catalase Enzyme in Myeloproliferative Neoplasm

“…Furthermore, we demonstrated that higher blood cell indices are associated with presence of JAK2-V617F mutation, a finding that indicates activated myelopoiesis [24]. In recent years, it has been demonstrated that superoxide anion as well as alkoxyl peroxyl and radicals could inactivate one of the antioxidant enzymes -catalase and reduce the effectiveness of cells to defend against free radical damage [25].…”