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Ferrata Storti Foundation
Haematologica 2021 Volume 106(7):1910-1922
Myeloproliferative Disorders
Crucial role of hematopoietic JAK2 V617F in the development of aortic aneurysms
Tetsuro Yokokawa,1,2 Tomofumi Misaka,1,3 Yusuke Kimishima,1 Kento Wada,1 Keiji Minakawa,4 Koichi Sugimoto,1,2 Takafumi Ishida,1 Soji Morishita,5 Norio Komatsu,6 Kazuhiko Ikeda4 and Yasuchika Takeishi,1
1Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima; 2Department of Pulmonary Hypertension, Fukushima Medical University, Fukushima; 3Department of Advanced Cardiac Therapeutics, Fukushima Medical University, Fukushima; 4Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University, Fukushima; 5Department of Transfusion Medicine and Stem Cell Regulation, Juntendo University Graduate School of Medicine, Tokyo and 6Department of Hematology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
ABSTRACT
JAK2 V617F is the most frequent driver mutation in myeloproliferative neoplasms (MPN) and is associated with vascular complications. However, the impact of hematopoietic JAK2 V617F on aortic aneurysms (AA) remains unknown. Our cross-sectional study indicated that nine (23%) of 39 MPN patients with JAK2 V617F exhibited the pres- ence of AA. In order to clarify whether the hematopoietic JAK2 V617F contributes to the AA, we applied bone marrow transplantation (BMT) with the donor cells from Jak2 V617F transgenic (JAK2V617F) mice or con- trol wild-type (WT) mice into lethally irradiated apolipoprotein E-defi- cient mice. Five weeks after BMT, the JAK2V617F-BMT mice and WT-BMT mice were subjected to continuous angiotensin II infusion to induce AA formation. Four weeks after angiotensin II infusion, the abdominal aorta diameter in the JAK2V617F-BMT mice was significantly enlarged compared to that in the WT-BMT mice. Additionally, the abdominal AA-free sur- vival rate was significantly lower in the JAK2V617F-BMT mice. Hematopoietic JAK2 V617F accelerated aortic elastic lamina degradation as well as activation of matrix metalloproteinase (MMP)-2 and MMP-9 in the abdominal aorta. The numbers of infiltrated macrophages were significantly upregulated in the abdominal aorta of the JAK2V617F-BMT mice accompanied by STAT3 phosphorylation. The accumulation of BM-derived hematopoietic cells carrying JAK2 V617F in the abdominal aorta was confirmed by use of the reporter green fluorescent protein- transgene. BM-derived macrophages carrying JAK2 V617F showed increases in mRNA expression levels of Mmp2, Mmp9, and Mmp13. Ruxolitinib decreased the abdominal aorta diameter and the incidence of abdominal AA in the JAK2V617F-BMT mice. Our findings provide a novel feature of vascular complications of AA in MPN with JAK2 V617F.
Introduction
Myeloproliferative neoplasms (MPN) including polycythemia vera (PV), essen- tial thrombocythemia (ET), and primary myelofibrosis (PMF) are characterized by chronic proliferation of mature myeloid cells and extramedullary hematopoiesis. The prevalence of MPN is reported to be 0.4 to 2.8 per 100,000 persons and the incident rates are 3.1 to 10.9 per one million person-years, which are increasing with age.1,2 Major causes of morbidity and mortality in MPN patients are repre- sented by vascular complications, progression to myelofibrosis, and transforma- tion to acute leukemia.3 To date, vascular disorders in MPN are known as arterial and venous thrombosis and advanced atherosclerosis.3-5 Among the MPN, JAK2 V617F is the most frequent driver mutation, which is observed in over 95% of PV patients as well as in 50–60% of ET and PMF patients.6 Several murine studies
Correspondence:
TOMOFUMI MISAKA
misaka83@fmu.ac.jp
KAZUHIKO IKEDA
kazu-ike@fmu.ac.jp
Received: June 24, 2020. Accepted: December 11, 2020. Pre-published: February 11, 2021.
https://doi.org/10.3324/haematol.2020.264085
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