Increased Adhesion Of CML Cells By ABL1 Tyrosine Kinase Inhibitors Induce Tunneling Nanotubes

The actin-containing cell-to-cell communicator tunneling nanotube (TNT) is suggested to be involved in regulation of cell death threshold of leukemic cells, while the mechanism of TNT regulation is mostly unknown. We have investigated TNT formation and its response to treatment with the tyrosine kinase inhibitors (imatinib and nilotinib) in chronic myeloid leukemia (CML) cells with the pathognomonic chimeric fusion kinase BCR-ABL1. Bone marrow cells of chronic phase CML patients and CML cell lines (Kcl-22 and K562) formed few or no TNTs. Imatinib treatment induced TNT formation in both cell lines and the induction of TNTs was found to be related to increased adherence to fibronectin coated surfaces by restoration of β1-integrin function. Co-culturing of Kcl-22 cells with stromal cells or conditioned medium inhibited the TKI-induced TNT formation. Interleukin-8 (CXCL8) secreted by the stromal cells was responsible for the TNT-inhibitory effect. This suggests modulation of TNT cell-cell communication in CML tumor-host interactions as a novel mechanism in kinase inhibitor therapy of CML.