Cell-to-cell communication is essential for the organization, coordination, and development of cellular networks and multi-cellular systems. Intercellular communication is mediated by soluble factors (including growth factors, neurotransmitters, and cytokines/chemokines), gap junctions, exosomes and recently described tunneling nanotubes (TNTs). It is unknown whether a combination of these communication mechanisms such as TNTs and gap junctions may be important, but further research is required. TNTs are long cytoplasmic bridges that enable long-range, directed communication between connected cells. The proposed functions of TNTs are diverse and not well understood but have been shown to include the cell-to-cell transfer of vesicles, organelles, electrical stimuli and small molecules. However, the exact role of TNTs and gap junctions for intercellular communication and their impact on disease is still uncertain and thus, the subject of much debate. The combined data from numerous laboratories indicate that some TNT mediate a long-range gap junctional communication to coordinate metabolism and signaling, in relation to infectious, genetic, metabolic, cancer, and age-related diseases. This review aims to describe the current knowledge, challenges and future perspectives to characterize and explore this new intercellular communication system and to design TNT-based therapeutic strategies.

Key Points• Primary BCP-ALL cells use tunneling nanotubes to signal to mesenchymal stromal cells and thereby trigger cytokine secretion.• Inhibiting tunneling nanotube signaling is a promising approach to induce apoptosis and sensitize BCP-ALL cells toward prednisolone.Acute lymphoblastic leukemia (ALL) cells reside in the bone marrow microenvironment which nurtures and protects cells from chemotherapeutic drugs. IntroductionAcute lymphoblastic leukemia (ALL) cells reside in the local microenvironment of the bone marrow and are able to disrupt normal hematopoietic stem cell niches.1 The disrupted, so-called leukemic, niche is essential in initiating and facilitating leukemogenesis. [2][3][4][5][6] In addition, the leukemic niche protects leukemic cells from elimination by immune responses and chemotherapeutic agents, and can facilitate the development of drug resistance of leukemic cells.7-10 Therefore, the disruption of the ALL-leukemic niche interaction offers a promising new therapeutic strategy.11-16 However, it is still largely unclear how crosstalk occurs within the leukemic niche, and how this drives leukemic cell survival and chemotherapy resistance.Recently, tunneling nanotubes (TNTs), or membrane nanotubes, have been described as a novel mode of communication between eukaryotic cells. [17][18][19][20][21] TNTs are thin membrane protrusions consisting of F-actin, that connect cells and facilitate the transport of several types of cargo, including organelles, pathogens, calcium fluxes, death signals, and membrane-bound proteins. 19,20,[22][23][24] These intercellular membrane conduits have been observed in several cell types, like cancer cells, complex tissues, and organisms. 20,21,[24][25][26][27][28][29] The pathophysiological importance of TNTs has become evident by studies showing that prions and HIV-1 particles use TNTs to promote disease spread. 21,30 However, the presence of TNTs within the leukemic niche and hence their role in communication between leukemic cells and the bone marrow microenvironment has not yet been addressed. Here, we study the role of TNT signaling in communication between primary B-cell precursor ALL (BCP-ALL) cells and mesenchymal stromal cells (MSCs), and the contribution of TNT signaling to mesenchymal-mediated survival and resistance to the chemotherapeutic drug prednisolone. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. For personal use only. on May 12, 2018. by guest www.bloodjournal.org From Primary patient-derived materialBone marrow aspirates were obtained from children with newly diagnosed BCP-ALL prior to treatment. Mononuclear leukemic cells were collected and processed as previously described. 31 All samples used in this study contained $97% leukemic blasts (supplemental Figure 7, see supplemental Data available at the Blood Web site). MSCs were isolated from bone marrow aspirates obtained from n...

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BdR and RP contributed equally to this work.