| First Author | Matsuura S | Year | 2020 |
| Journal | Blood | Volume | 135 |
| Issue | 25 | Pages | 2286-2291 |
| PubMed ID | 32294178 | Mgi Jnum | J:301286 |
| Mgi Id | MGI:6503700 | Doi | 10.1182/blood.2019004230 |
| Citation | Matsuura S, et al. (2020) Adhesion to fibronectin via alpha5beta1 integrin supports expansion of the megakaryocyte lineage in primary myelofibrosis. Blood 135(25):2286-2291 |
| abstractText | Excessive accumulation of extracellular matrix (ECM) is a hallmark of bone marrow (BM) milieu in primary myelofibrosis (PMF). Because cells have the ability to adhere to the surrounding ECM through integrin receptors, we examined the hypothesis that an abnormal ECM-integrin receptor axis contributes to BM megakaryocytosis in JAK2V617F+ PMF. Secretion of ECM protein fibronectin (FN) by BM stromal cells from PMF patients correlates with fibrosis and disease severity. Here, we show that Vav1-hJAK2V617F transgenic mice (JAK2V617F+) have high BM FN content associated with megakaryocytosis and fibrosis. Further, megakaryocytes from JAK2V617F+ mice have increased cell surface expression of the alpha5 subunit of the alpha5beta1 integrin, the major FN receptor in megakaryocytes, and augmented adhesion to FN compared with wild-type controls. Reducing adhesion to FN by an inhibitory antibody to the alpha5 subunit effectively reduces the percentage of CD41+ JAK2V617F+ megakaryocytes in vitro and in vivo. Corroborating our findings in mice, JAK2V617F+ megakaryocytes from patients showed elevated expression of alpha5 subunit, and a neutralizing antibody to alpha5 subunit reduced adhesion to FN and megakaryocyte number derived from CD34+ cells. Our findings reveal a previously unappreciated contribution of FN-alpha5beta1 integrin to megakaryocytosis in JAK2V617F+ PMF. |
