Abstract
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.
Highlights
Galectins are lectins that specialize in the recognition of galactose-containing structures
We recently showed that B-cell precursor acute lymphoblastic leukemia cells derived from galectin3-/- mice are more sensitive to drug treatment than wild type cells, and that overexpression of Galectin-3 by retroviral transduction protects pre-B ALL cells against drug treatment [6]
Since we previously found that the development of environmentally-mediated drug resistance (EMDR) in ALL-stromal co-culture models correlates with a profile of increased expression of genes typically associated with inflammation [23], we investigated the effect of chemotherapy on Galectin-3 levels in co-cultures of stromal and leukemia cells
Summary
Galectins are lectins that specialize in the recognition of galactose-containing structures. Galectin-3 (Lgals3) is a 30 kDa lectin that has cross-linking and lattice-promoting activity, through combination of an N-terminal domain that allows oligomerization with a. C-terminal carbohydrate binding domain [1]. Galectin-3 is found extracellularly but is present in the cytoplasm, and in the nucleus. Its carbohydrate-binding ability appears to be critical for extracellular functions, whereas intracellular Galectin-3 has many effects and molecular interactions that are largely carbohydrateindependent [2]. Elevated Galectin-3 www.impactjournals.com/oncotarget levels are associated with numerous types of cancer, and frequently correlate with poor outcome [3,4,5]. Inflammatory processes often are associated with elevated Galectin-3. The cellular origin of, and the reasons for increased Galectin-3 levels are poorly understood
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