Tyrosine kinase inhibitors and interferon‐α increase tunneling nanotube (TNT) formation and cell adhesion in chronic myeloid leukemia (CML) cell lines

Abstract

Chronic myeloid leukemia (CML) is a stem cell disease of the bone marrow where mechanisms of inter‐leukemic communication and cell‐to‐cell interactions are proposed to be important for optimal therapy response. Tunneling nanotubes (TNTs) are novel intercellular communication structures transporting different cargos with potential implications in therapy resistance. Here, we have investigated TNTs in CML cells and following treatment with the highly effective CML therapeutics tyrosine kinase inhibitors (TKIs) and interferon‐α (IFNα). CML cells from chronic phase CML patients as well as the blast crisis phase cell lines, Kcl‐22 and K562, formed few or no TNTs. Treatment with imatinib increased TNT formation in both Kcl‐22 and K562 cells, while nilotinib or IFNα increased TNTs in Kcl‐22 cells only where the TNT increase was associated with adherence to fibronectin‐coated surfaces, altered morphology, and reduced movement involving β1integrin. Ex vivo treated cells from chronic phase CML patients showed limited changes in TNT formation similarly to bone marrow cells from healthy individuals. Interestingly, in vivo nilotinib treatment in a Kcl‐22 subcutaneous mouse model resulted in morphological changes and TNT‐like structures in the tumor‐derived Kcl‐22 cells. Our results demonstrate that CML cells express low levels of TNTs, but CML therapeutics increase TNT formation in designated cell models indicating TNT functionality in bone marrow derived malignancies and their microenvironment.

Specialized Intercellular Communications via Tunnelling Nanotubes in Acute and Chronic Leukemia

“…The fact that the administration of imatinib did not cause an increase in TNT formation in BCR-ABL1 cells presenting Ba/F3, but rather in Ba/F3 cells alone, indicates that the increase in TNT most likely involves other elements besides the inhibition of BCR-ABL1. This was also demonstrated by the evaluation of intracellular signaling through mass cytometry, in which known BCR-ABL1 targets, such as phospho-STAT-5, were reduced by TKI administration, regardless of the reported differences in TNT response [155].…”

“…A different study evaluated TNTs in CML cells after the administration of tyrosine kinase inhibitors (TKIs) and interferon-α (IFNα) [155]. It was demonstrated that CML cells from patients in chronic phase or from blast crisis phase cell lines, Kcl-22 and K562, generated scarce or no TNTs.…”

Importance of Crosstalk Between Chronic Lymphocytic Leukemia Cells and the Stromal Microenvironment: Direct Contact, Soluble Factors, and Extracellular Vesicles

“…Coculture of leukemic cells with MSCs is associated with actin polymerization (71,82) and consequent cytoskeletal remodeling in CLL cells. For other leukemias such as chronic myeloid leukemia (83,84) and acute lymphoblastic leukemia (85)(86)(87), tunneling nanotubes have been identified as a novel mode of intercellular crosstalk. Tunneling nanotubes are long and thin membranous structures that allow the exchange of material [such as mitochondria (85), vesicles or proteins (83)] between leukemic cells and stromal cells.…”

Tunneling Nanotubes: A New Target for Nanomedicine?

“…The exchange of misfolded proteins and damaged genetic material through TNTs in cancers is considered one of the major phenomena that contribute to the transformation of healthy cells into tumoral cells and increases in metastasis formation [5,27]. While TNTs have been linked to communication and spreading in several types of cancer [28], such as prostate [29], bladder [30][31][32], pancreatic [33], and breast cancer [34], as well as different types of leukemia [35][36][37]. Glioblastoma multiforme (GBM) is by far the most studied for the consequences of TNT activity [4,38].…”