B-cell precursor acute lymphoblastic leukemia and stromal cells communicate through Galectin-3
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Fei Fei1,2, Eun Ji Joo1,2, Somayeh S. Tarighat1,2, Isabelle Schiffer1,2, Helicia Paz1,2, Muller Fabbri3, Hisham Abdel-Azim2, John Groffen1,2,4,5, Nora Heisterkamp1,2,4,5
1Section of Molecular Carcinogenesis, Division of Hematology/Oncology and Bone Marrow Transplant, The Saban Research Institute of Children’s Hospital Los Angeles, Los Angeles, CA, USA
2Division of Hematology/Oncology and Bone Marrow Transplant, Children’s Hospital Los Angeles, Los Angeles, CA, USA
3Department of Pediatrics, Molecular Microbiology and Immunology, Keck School of Medicine, Norris Comprehensive Cancer Center, Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA
4Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, Los Angeles, CA, USA
5Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
Nora Heisterkamp, e-mail: [email protected]
Keywords: Lgals3, stroma, drug resistance, exosomes, microenvironment
Received: July 29, 2014 Accepted: February 19, 2015 Published: March 30, 2015
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.
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