Fei Fei, Joo Eun Ji, Tarighat Somayeh S, Schiffer Isabelle, Paz Helicia, Fabbri Muller, Abdel-Azim Hisham, Groffen John, Heisterkamp Nora
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.
Oncotarget. 2015 May 10;6(13):11378-94. doi: 10.18632/oncotarget.3409.
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.
骨髓中B细胞前体急性淋巴细胞白血病（pre - B ALL）细胞与基质细胞之间的分子相互作用，这种相互作用提供了微环境介导的对治疗药物的保护作用，但目前尚未明确。半乳糖凝集素-3（Lgals3）是一种多功能的半乳糖结合凝集素，据报道在不同细胞类型的细胞核、细胞质和细胞外空间均有分布。我们之前报道过，与基质共同培养的ALL细胞中含有高水平的半乳糖凝集素-3。我们在此确定，与更成熟的B系癌症不同，在ALL细胞内及表面检测到的半乳糖凝集素-3源自基质细胞，基质细胞在其表面表达该蛋白，将其作为可溶性蛋白分泌，同时也分泌到外泌体中。可溶性和与基质结合的半乳糖凝集素-3被ALL细胞内化，转运至细胞核并刺激内源性LGALS3 mRNA的转录。当人和小鼠ALL细胞在与保护性基质细胞接触时对不同药物产生耐受性时，半乳糖凝集素-3蛋白水平持续升高。这与ALL细胞中半乳糖凝集素-3转录的诱导相关。因此，源自基质的半乳糖凝集素-3在受到药物治疗持续压力的pre - B ALL细胞中，会被内源性半乳糖凝集素-3的产生所补充。我们的数据表明，基质半乳糖凝集素-3可能通过半乳糖凝集素-3 mRNA的自诱导和持续性NFκB途径激活来保护ALL细胞。由于内源性合成的半乳糖凝集素-3可保护pre - B ALL细胞免受药物治疗，我们将半乳糖凝集素-3确定为一种可能抵消基质保护作用的靶点。
