Adhesion to fibronectin via α5β1 integrin supports expansion ...

MYELOID NEOPLASIA| JUNE 18, 2020

Adhesion to fibronectin via α5β1 integrin supports expansion of the megakaryocyte lineage in primary myelofibrosis

Shinobu Matsuura, Cristal Reyna Thompson, Seng Kah Ng, Christina Marie Ward, Aikaterini Karagianni, Carla Mazzeo, Alessandro Malara, Alessandra Balduini, Katya Ravid

Blood (2020) 135 (25): 2286–2291.

https://doi.org/10.1182/blood.2019004230

Key Points

The α5 subunit of α5β1 integrin is upregulated in JAK2V617F+ megakaryocytes in PMF leading to increased adhesion to fibronectin.

Antibody-mediated inhibition of the α5 subunit prevents expansion of megakaryocyte lineage in JAK2V617F+ cells in vitro and in vivo.

Abstract

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 α5 subunit of the α5β1 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 α5 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 α5 subunit, and a neutralizing antibody to α5 subunit reduced adhesion to FN and megakaryocyte number derived from CD34+ cells. Our findings reveal a previously unappreciated contribution of FN-α5β1 integrin to megakaryocytosis in JAK2V617F+ PMF.

Subjects:

Brief Reports, Hematopoiesis and Stem Cells, Myeloid Neoplasia

Topics:

adhesions, antibodies, fibronectins, integrins, megakaryocytes, myelofibrosis, idiopathic, chronic, mice

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