![]() The BCR-ABL1 protein contains an F-actin binding domain and orchestrates several cellular processes including actin processing, cell attachment to fibronectin and cell migration. 41 Subsequently, TNTs have been proposed to be implicated in disease and to play a role with respect to therapy response recently demonstrated by vesicle exchange from stromal cells to CML cells providing increased resistance to imatinib. 33- 38 The impact of TNTs in vivo is so far not well characterized, but they have been described to connect myeloid cells in the cornea of mouse 39, 40 and in fresh resected tumor samples from patients with malignant pleural mesothelioma and lung adenocarcinoma. 25- 32 TNT is proposed to be a mechanism for chemo resistance by transport of oncoproteins between T and B cells as well as in colon cancer cells, by transfer of mitochondria from endothelial cells to chemotherapy exposed cancer cells, or by induced drug-efflux in aggressive forms of pancreatic carcinoma. 16, 18- 24 Leukocytes, their leukemic counterparts and bone marrow stromal cells have all been reported to form TNTs in vitro. 16, 17 They are involved in cell-to-cell interaction and intercellular transport of organelles and pathogens such as virus and bacteria. ![]() 16 TNTs are defined as thin (50-200 nm), fragile, and dynamic structures, consisting of plasma membrane and filamentous (F)-actin. 15 One modality of physical cell-to-cell interaction is the tunneling nanotube (TNT). It is well established that the tumor microenvironment and its cell-to-cell interactions play a pivotal role in the outcome of cancer therapy. 6- 8 The role of BCR-ABL1 in microenvironment dependent cellular communication is less understood 9- 11 particularly in the context of the efficient therapies with small molecule kinase inhibitors. T.n.t. rabbitry series#5 Imatinib was the first of a series of BCR-ABL1-targeted drugs used in treatment of CML patients, and these inhibitors vary based on potency, efficiency on mutated ABL1 and have different adverse effect profiles. 3, 4 This was the first-line treatment of choice for CML prior to the introduction of the tyrosine kinase inhibitor (TKI) imatinib in 2000, but IFNα is now gaining enhanced interest in combination treatments with imatinib and other TKIs. 1, 2 The introduction of IFNα revolutionized the treatment of CML and initial studies performed in 1980s by Talpaz and colleagues resulted in the first evidence of induced hematological remission and cytogenetic responses in a subset of treated patients. Initially, CML treatment included interferon-α (IFNα) and hematopoietic stem cell transplantation. ![]() 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.Ĭhronic myeloid leukemia (CML) is a myeloid stem cell disease characterized by the tyrosine kinase BCR-ABL1 fusion protein derived from the chromosomal translocation t (9 22), involving bone marrow and spleen in the chronic phase. 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. Ex vivo treated cells from chronic phase CML patients showed limited changes in TNT formation similarly to bone marrow cells from healthy individuals. ![]() 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. 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. 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). Tunneling nanotubes (TNTs) are novel intercellular communication structures transporting different cargos with potential implications in therapy resistance. 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. ![]()
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