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T. Yokokawa et al.
Table 1. Characteristics and prevalence of aortic aneurysms in JAK2 V617F-positive myeloproliferative neoplasm patients. All patients Thrombosis (+) Thrombosis (-)
(n=39) (n=10) (n=29)
Age,years 68±12 73±9 66±13
P
0.118
0.468
0.141 0.130 0.591
0.270 0.889 0.213 0.939
0.332
0.456 0.510 0.007 0.440
<0.001 0.013
0.014
0.744
0.032 0.057 0.452
Female, n. (%)
MPN diagnosis
Polycythemia vera, n. (%) Essential thrombocythemia, n. (%) Primary myelofibrosis, n. (%)
Laboratory data
White blood cell count, ×109/L Red blood cell count, ×1012/L Hemoglobin concentration, g/dL Platelet count, ×109/L
JAK2 V617F allele burden, % Comorbidities Hypertension, n. (%) Diabetes mellitus, n. (%) Dyslipidemia, n. (%) Smoking history, n. (%) Thrombosis history
Arterial thrombosis, n. (%) Venous thrombosis, n. (%)
Cytoreductive treatment Hydroxyurea, n. (%) Ruxolitinib, n. (%)
Presence of aortic aneurysms Thoracic aortic aneurysm, n. (%) Abdominal aortic aneurysm, n. (%)
21 (54)
16 (41) 12 (31) 11 (28)
6 (60)
2 (20) 5 (50) 3 (30)
15 (52)
14 (48) 7 (24) 8 (28)
10.6 ± 5.5
14.0 ± 3.9 12.7 ± 3.0 14.5 ± 4.0
509±427 500±270 512±473 51±30 43±33 53±29
13.5 ± 9.4
4.7±1.5 4.6±1.3 4.7±1.6
17 (44) 6 (15) 7 (18) 13 (33)
7 (18) 3 (8)
17 (44)
1 (3)
9 (23) 7 (18) 2 (5)
5 (50) 1 (10) 5 (50) 4 (40)
7 (70) 3 (30)
1 (10)
0 (0)
5 (50) 4 (40) 1 (10)
12 (41) 5 (17) 2 (7) 9 (31)
0 (0) 0 (0)
16 (55)
1 (3)
4 (14) 3 (10) 1 (3)
14.5 ± 10.4
events in PV and ET,28,29 the prevalence of AA was signif- icantly higher in the JAK 2V617F-positive MPN patients with a history of thrombosis than in those without (Table 1 and Online Supplementary Table S1). Next, we examined the expression levels of genes known to be related to AA, such as MMP and cytokines,30 in circulating leukocytes. The MMP9, which is independently associated with aor- tic wall thickness and aortic luminal diameter during the process of AA,31 as well as TGFB3 and in interleukin 8 (IL- 8) were significantly increased in JAK2 V617F-positive MPN patients compared to the age- and sex-matched control subjects (Online Supplementary Figure S1 and Online Supplementary Table S2). These findings suggest that incidences of AA are not rare in JAK2 V617F-positive MPN patients, and that the presence of JAK2 V617F in leukocytes may lead to increases in the expression levels of genes involved in the pathogenesis of AA.
Hematopoietic JAK2 V617F promotes abdominal aortic aneurysms formation in angiotensin II-infused ApoE−/− mice
In order to clarify whether or not hematopoietic Jak2 V617F could indeed play a mechanistic role in the devel- opment of AA, we applied the BMT strategy using the donor BM cells from the JAK2V617F mice7 into the lethally irradiated ApoE−/− mice24 (JAK2V617F-BMT mice) (Figure 1A). The irradiated ApoE−/− recipient mice transplanted with donor BM cells from WT littermates (WT-BMT mice) were used as controls. Five weeks after BMT, the donor cells were similarly engrafted as shown in the chimeric analysis of the peripheral blood cells between the WT-BMT mice and JAK2V617F-BMT mice (Figure 1B).
The JAK2V617F-BMT mice displayed significantly higher white blood cell counts and spleen weights compared to the WT-BMT mice, indicating a hematological feature of MPN-like phenotype in the JAK2V617F-BMT mice (Figure 1C and Online Supplementary Figure S2). Next, the WT- BMT mice and JAK2V617F-BMT mice were continuously infused with Ang II with 1900 ng/kg/min for 4 weeks, as a higher dose of Ang II is required to induce the AA for- mation when the irradiated ApoE−/− recipient mice are used.24 At 2 and 4 weeks following Ang II infusion, sys- tolic, mean, and diastolic blood pressures were all signif- icantly increased compared to those of the saline groups, but there were no differences in these parameters between the WT-BMT mice and JAK2V617F-BMT mice (Figure 1D; Online Supplementary Figure S3A and S3B). No significant difference was observed regarding the heart rate between the WT-BMT mice and JAK2V617F-BMT mice after Ang II infusion (Online Supplementary Figure S3C). Total cholesterol and triglyceride concentrations were decreased in the JAK2V617F-BMT mice compared to WT- BMT mice (Online Supplementary Table S3), in agreement with the findings that MPN patients with JAK2 V617F often display low lipid profiles that correlate with advanced disease.32,33 Chimerism was not significantly different between the WT-BMT mice and JAK2V617F-BMT mice 4 weeks after saline or Ang II infusion (Online Supplementary Figure S3D). We monitored both the tho- racic aorta and suprarenal abdominal aorta by ultra- sonography. The presence of TAA and AAA was defined as an increase by ≥50% in aortic diameter in comparison to the baseline. We did not observe any significant differ- ences in the thoracic aorta diameter or the incidence of
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