Acute lymphoblastic leukemia (ALL) cells reside in the bone marrow microenvironment which nurtures and protects cells from chemotherapeutic drugs. The disruption of cellcell communication within the leukemic niche may offer an important new therapeutic strategy. Tunneling nanotubes (TNTs) have been described as a novelmode of intercellular communication, but their presence and importance in the leukemic niche are currently unknown. Here,we showfor the first time that primary B-cell precursor ALL (BCP-ALL) cells use TNTs to signal to primary mesenchymal stromal cells (MSCs). This signaling results in secretion of prosurvival cytokines, such as interferon-γ-inducible protein 10/CXC chemokine ligand 10, interleukin 8, and monocyte chemotactic protein-1/CC chemokine ligand 2. A combination of TNT-disrupting conditions allows us to analyze the functional importance of TNTs in an ex vivomodel.Our results indicate that TNTsignaling is important for the viability of patient-derived B-cell precursor ALL cells and induces stroma-mediated prednisolone resistance. Disruption of TNTs significantly inhibits these leukemogenic processes and resensitizes B-cell precursor ALL cells to prednisolone. Our findings establish TNTs as a novel communication mechanism by which ALL cells modulate their bone marrow microenvironment. The identification of TNT signaling in ALL-MSC communication gives insight into the pathobiology of ALL and opens new avenues to develop more effective therapies that interfere with the leukemic niche.,
Department of Pediatrics

Polak, R, de Rooij, B, Pieters, R, & den Boer, M.L. (2015). B-cell precursor acute lymphoblastic leukemia cells use tunneling nanotubes to orchestrate their microenvironment. Blood, 126(21), 2404–2414. doi:10.1182/blood-2015-03-634238