JAK2 tyrosine kinase mediates integrin activation induced by CXCL12 in B-cell chronic lymphocytic leukemia

• DOI: 10.18632/oncotarget.5196
• Publication Date: 2015-09-29T21:54:23Z
• Authors: Alessio Montresor; Lara Toffali; Michela Mirenda; Antonella Rigo; Fabrizio Vinante; Carlo Laudanna
• Keywords: Adult; Aged, 80 and over; Male; 0301 basic medicine; B-Lymphocytes; Integrins; JAKs; adhesion; chemokines; chronic lymphocytic leukemia; integrin activation; Blotting, Western; Enzyme-Linked Immunosorbent Assay; Janus Kinase 2; Middle Aged; Transfection; Leukemia, Lymphocytic, Chronic, B-Cell; Chemokine CXCL12; Lymphocyte Function-Associated Antigen-1; 03 medical and health sciences; Cell Adhesion; Humans; Female; RNA, Small Interfering; Aged; Signal Transduction

Chemokines participate to B-cell chronic lymphocytic leukemia (B-CLL) pathogenesis by promoting cell adhesion and survival in bone marrow stromal niches and mediating cell dissemination to secondary lymphoid organs. In this study we investigated the role of JAK protein tyrosine kinases (PTK) in adhesion triggering by the CXC chemokine CXCL12 in normal versus CLL B-lymphocytes. We demonstrate that CXCL12 activates JAK2 in normal as well as CLL B-lymphocytes, with kinetics consistent with rapid adhesion triggering. By using complementary methodologies of signal transduction interference, we found that JAK2 mediates CXCL12-triggered activation of lymphocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4) integrins. We also show that JAK2 mediates the activation of the small GTP-binding protein RhoA, in turn controlling LFA-1 affinity triggering by CXCL12. Importantly, comparative analysis of 41 B-CLL patients did not evidence JAK2 functional variability between subjects, thus suggesting that JAK2, differently from other signaling events involved in adhesion regulation in B-CLL, is a signaling molecule downstream to CXCR4 characterized by a conserved regulatory role. Our results reveal JAK2 as critical component of chemokine signaling in CLL B-lymphocytes and indicate JAK inhibition as a potentially useful new pharmacological approach to B-CLL treatment.