B-cell precursor acute lymphoblastic leukemia and stromal cells communicate through Galectin-3

• Published in: Oncotarget Vol. 6; no. 13; pp. 11378 - 11394
• Main Authors: Fei, Fei, Joo, Eun Ji, Tarighat, Somayeh S, Schiffer, Isabelle, Paz, Helicia, Fabbri, Muller, Abdel-Azim, Hisham, Groffen, John, Heisterkamp, Nora
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 10.05.2015
• Subjects: Active Transport, Cell Nucleus; Animals; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Endocytosis; Exosomes - metabolism; Galectin 3 - deficiency; Galectin 3 - genetics; Galectin 3 - metabolism; Gene Expression Regulation, Leukemic; Humans; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B - metabolism; Paracrine Communication - drug effects; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Research Paper; RNA, Messenger - metabolism; Signal Transduction - drug effects; Stromal Cells - metabolism; Stromal Cells - pathology; Time Factors; Transcription, Genetic; Transcriptional Activation; Transfection; Tumor Microenvironment; microenvironment; drug resistance; exosomes; stroma; Lgals3
• DOI: 10.18632/oncotarget.3409
• ISSN: 1949-2553

The molecular interactions between B-cell precursor acute lymphoblastic leukemia (pre-B ALL) cells and stromal cells in the bone marrow that provide microenvironmentally-mediated protection against therapeutic drugs are not well-defined. Galectin-3 (Lgals3) is a multifunctional galactose-binding lectin with reported location in the nucleus, cytoplasm and extracellular space in different cell types. We previously reported that ALL cells co-cultured with stroma contain high levels of Galectin-3. We here establish that, in contrast to more mature B-lineage cancers, Galectin-3 detected in and on the ALL cells originates from stromal cells, which express it on their surface, secrete it as soluble protein and also in exosomes. Soluble and stromal-bound Galectin-3 is internalized by ALL cells, transported to the nucleus and stimulates transcription of endogenous LGALS3 mRNA. When human and mouse ALL cells develop tolerance to different drugs while in contact with protective stromal cells, Galectin-3 protein levels are consistently increased. This correlates with induction of Galectin-3 transcription in the ALL cells. Thus Galectin-3 sourced from stroma becomes supplemented by endogenous Galectin-3 production in the pre-B ALL cells that are under continuous stress from drug treatment. Our data suggest that stromal Galectin-3 may protect ALL cells through auto-induction of Galectin-3 mRNA and tonic NFκB pathway activation. Since endogenously synthesized Galectin-3 protects pre-B ALL cells against drug treatment, we identify Galectin-3 as one possible target to counteract the protective effects of stroma.