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Editorials
tant. Here, the authors perform a prevalence study in 39 JAK2 V617F-positive MPN patients, and found that 23% displayed signs of AA. Intriguingly, they find that JAK2 V617-positive circulating leukocytes demonstrated up- regulation of genes associated with AA, including matrix metalloproteinase 9 (MMP-9), which plays a well-estab- lished role in AA. This finding provided the authors’ first insight into the potential mechanism underlying JAK2 V617F-mediated AA.
In order to further understand the role that hematopoi- etic-derived JAK2 V617F plays in the development of AA, the authors turn to a well characterized bone marrow transplantation (BMT) model of JAK2 V617F-driven MPN, in which JAK2 V617F expression is restricted to donor BM cells. Here, the authors utilize mice deficient in apolipoprotein E (ApoE-/-) as recipients, and subject them to continuous infusion of angiotensin II (AngII), a model that has been shown to promote development and expan- sion of AA. In their endpoint analysis, the authors com- pare animals receiving wild-type (WT) versus JAK2 V617F-expressing BM cells, and find that, in addition to the expected MPN-like phenotype, JAK2 V617F BMT mice exhibit significantly increased abdominal aorta diameter, indicative of abdominal AA (AAA). Moreover, they find that JAK2 V617F expression accelerated the AAA hallmark of arterial extracellular matrix proteolysis as measured by aortic elastic lamina degradation, and led to activation of MMP-9 as well as MMP-2 in the abdom- inal aorta, both of which are required to produce AAA. Together, these results suggest that BM-derived JAK2 V617F promotes the development of AAA.
Digging deeper into the molecular mechanism underly- ing how JAK2 V617F leads to the development of AAA, the authors find infiltration of JAK2 V617F-mutant inflamma- tory cells, including CD68+ macrophages and Ly6B.2+ neutrophils, as well as increased phosphorylation of JAK2 V617F target STAT3, in the abdominal aortas of JAK2 V617F BMT mice receiving AngII. They go on to show that the inflammatory cells are strictly BM-derived, confirming that it is indeed hematopoietic JAK2 V617F causing the development of AAA in these animals. Finally and most intriguingly, they show that JAK2 V617F BM-derived CD68+ macrophages exhibit significantly increased mRNA expression levels of Mmp2 and Mmp9, both of which could be decreased upon treatment with the JAK2 inhibitor ruxolitinib. Additionally, AngII-treated JAK2
V617F BMT mice treated with ruxolitinib experienced decreased incidence of AAA. These data suggest that JAK2 V617F promotes activation of MMP in BM-derived inflam- matory cells, which leads to AAA development (Figure 1).
Taken together, the results from this study identify a novel vascular disorder associated with JAK2 V617F mutations, provide a direct link between JAK2 V617F and the pathogenesis of AAA, and offer an additional thera- peutic application for Food and Drug Admionstration- approved JAK2 inhibitors in the prevention of AAA development in JAK2 V617F-positive MPN patients.
Disclosures
No conflicts of interest to disclose.
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