title: B-cell precursor acute lymphoblastic leukemia and stromal cells communicate through Galectin-3.
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.
authors: Section 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.|Division of Hematology/Oncology and Bone Marrow Transplant, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors: Fei
authors: F
authors: Fei
authors: Section 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.|Division of Hematology/Oncology and Bone Marrow Transplant, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors: Eun Ji
authors: EJ
authors: Joo
authors: Section 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.|Division of Hematology/Oncology and Bone Marrow Transplant, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors: Somayeh S
authors: SS
authors: Tarighat
authors: Section 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.|Division of Hematology/Oncology and Bone Marrow Transplant, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors: Isabelle
authors: I
authors: Schiffer
authors: Section 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.|Division of Hematology/Oncology and Bone Marrow Transplant, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors: Helicia
authors: H
authors: Paz
authors: Department 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.
authors: Muller
authors: M
authors: Fabbri
authors: Division of Hematology/Oncology and Bone Marrow Transplant, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors: Hisham
authors: H
authors: Abdel-Azim
authors: Section 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.|Division of Hematology/Oncology and Bone Marrow Transplant, Children's Hospital Los Angeles, Los Angeles, CA, USA.|Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, Los Angeles, CA, USA.|Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors: John
authors: J
authors: Groffen
authors: Section 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.|Division of Hematology/Oncology and Bone Marrow Transplant, Children's Hospital Los Angeles, Los Angeles, CA, USA.|Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, Los Angeles, CA, USA.|Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors: Nora
authors: N
authors: Heisterkamp
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001798:Blood Proteins; D045744:Cell Line, Tumor; D004705:Endocytosis; D055354:Exosomes / Q000378:metabolism; D037502:Galectin 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D037161:Galectins; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D019899:Paracrine Communication / Q000187:drug effects; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D001798:Blood Proteins; D037502:Galectin 3; D037161:Galectins; C428445:LGALS3 protein, human; C485095:Lgals3 protein, mouse; D016328:NF-kappa B; D012333:RNA, Messenger
keywords: Lgals3; drug resistance; exosomes; microenvironment; stroma