Influence of the JAK2-V617F mutation on integrin-mediated adhesion to VCAM1 in murine and human cell lines in the context of classical Philadelphia-negative myeloproliferative neoplasms

Abstract

JAK2-V617F is an activating point mutation of the intracellular tyrosine kinase JAK2 and the most prevalent mutation in patients suffering from Philadelphia-negative myeloproliferative neoplasm (MPN). Besides debilitating constitutional symptoms, myelofibrosis, and leukemic transformation, the MPN phenotype comprises extramedullary hematopoiesis and an increased risk for arterial and venous thrombosis. JAK2 has recently been shown to mediate chemokine-induced activation of integrin adhesion molecules thereby enabling increased cell adhesion and tissue-specific homing of leukocytes. By using an overexpression model of JAK2-V617F in murine BaF3 cells and JAK2-V617F-positive human HEL cells treated with JAK2-specific kinase inhibitors or shRNAs, we herein demonstrate that aberrant JAK2-V617F signaling is associated with increased integrin-mediated cell adhesion to Vascular Cell Adhesion Molecule 1 (VCAM1). In BaF3 cells, an increase in integrin affinity to VCAM1, but not regulation of β1-integrin surface expression, seems to contribute to the mechanism underlying the adhesion phenotype. We argue that the observed enhancement of integrin-mediated cell adhesion in JAK2-V617F-positive cells might contribute to the clinical phenomena of thrombosis and extramedullary hematopoiesis occurring in MPN patients and, hence, deserve to be studied in more detail.