title: A role for reactive oxygen species in JAK2 V617F 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.
authors.affiliation: 1] Institut National de la Santé et de la Recherche Médicale, UMR1009, Laboratory of Excellence GR-Ex, Villejuif, France [2] INSERM U1009, PR1, Institut Gustave Roussy, Villejuif, France [3] University Paris-Sud 11, Le Kremlin-Bicêtre, France.
authors.forename: C
authors.initials: C
authors.lastname: Marty
authors.forename: C
authors.initials: C
authors.lastname: Lacout
authors.forename: N
authors.initials: N
authors.lastname: Droin
authors.forename: J-P
authors.initials: JP
authors.lastname: Le Couédic
authors.forename: V
authors.initials: V
authors.lastname: Ribrag
authors.forename: E
authors.initials: E
authors.lastname: Solary
authors.forename: W
authors.initials: W
authors.lastname: Vainchenker
authors.forename: J-L
authors.initials: JL
authors.lastname: Villeval
authors.forename: I
authors.initials: I
authors.lastname: Plo
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D016022:Case-Control Studies; D004249:DNA Damage / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D053614:Janus Kinase 2 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017354:Point Mutation / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000975:Antioxidants; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt; D000111:Acetylcysteine