title: B-cell precursor acute lymphoblastic leukemia cells use tunneling nanotubes to orchestrate their microenvironment.
abstract: Acute lymphoblastic leukemia (ALL) cells reside in the bone marrow microenvironment which nurtures and protects cells from chemotherapeutic drugs. The disruption of cell-cell communication within the leukemic niche may offer an important new therapeutic strategy. Tunneling nanotubes (TNTs) have been described as a novel mode of intercellular communication, but their presence and importance in the leukemic niche are currently unknown. Here, we show for 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 vivo model. Our results indicate that TNT signaling 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.
authors: Department of Pediatric Oncology, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands; and.
authors: Roel
authors: http://orcid.org/0000-0001-7815-1202
authors: R
authors: Polak
authors: Department of Pediatric Oncology, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands; and.
authors: Bob
authors: http://orcid.org/0000-0002-6424-0025
authors: B
authors: de Rooij
authors: Department of Pediatric Oncology, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands; and Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
authors: Rob
authors: R
authors: Pieters
authors: Department of Pediatric Oncology, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands; and.
authors: Monique L
authors: ML
authors: den Boer
mesh_terms: D000293:Adolescent; D002450:Cell Communication; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D043942:Nanotubes; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D011239:Prednisolone / Q000494:pharmacology; D059016:Tumor Microenvironment
chemical_list: D016207:Cytokines; D011239:Prednisolone