{"doi":"10.3390/ijms222212167","title":"Overcoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic Leukemia","abstract":"Environmentally-mediated drug resistance in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) significantly contributes to relapse. Stromal cells in the bone marrow environment protect leukemia cells by secretion of chemokines as cues for BCP-ALL migration towards, and adhesion to, stroma. Stromal cells and BCP-ALL cells communicate through stromal galectin-3. Here, we investigated the significance of stromal galectin-3 to BCP-ALL cells. We used CRISPR/Cas9 genome editing to ablate galectin-3 in stromal cells and found that galectin-3 is dispensable for steady-state BCP-ALL proliferation and viability. However, efficient leukemia migration and adhesion to stromal cells are significantly dependent on stromal galectin-3. Importantly, the loss of stromal galectin-3 production sensitized BCP-ALL cells to conventional chemotherapy. We therefore tested novel carbohydrate-based small molecule compounds (Cpd14 and Cpd17) with high specificity for galectin-3. Consistent with results obtained using galectin-3-knockout stromal cells, treatment of stromal-BCP-ALL co-cultures inhibited BCP-ALL migration and adhesion. Moreover, these compounds induced anti-leukemic responses in BCP-ALL cells, including a dose-dependent reduction of viability and proliferation, the induction of apoptosis and, importantly, the inhibition of drug resistance. Collectively, these findings indicate galectin-3 regulates BCP-ALL cell responses to chemotherapy through the interactions between leukemia cells and the stroma, and show that a combination of galectin-3 inhibition with conventional drugs can sensitize the leukemia cells to chemotherapy.","journal":"International Journal of Molecular Sciences","year":2021,"id":190443,"datarank":0.5336376281197132,"base_score":2.70805020110221,"endowment":2.70805020110221,"self_citation_contribution":0.40620753016533157,"citation_network_contribution":0.1274300979543816,"self_endowment_contribution":0.40620753016533157,"citer_contribution":0.1274300979543816,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":12,"citers_with_citation_signal":9,"citers_with_endowment":9,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9535,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":754585,"name":"Fei Fei","orcid":"0000-0002-6815-7931","position":1,"is_corresponding":false},{"id":755307,"name":"Eun Ji Joo","orcid":null,"position":2,"is_corresponding":false},{"id":249842,"name":"Hisham Abdel‐Azim","orcid":"0000-0003-0880-8701","position":3,"is_corresponding":false},{"id":415521,"name":"Lu Yang","orcid":"0000-0001-7952-0399","position":4,"is_corresponding":false},{"id":272482,"name":"Huimin Geng","orcid":"0000-0001-5339-5446","position":5,"is_corresponding":false},{"id":456382,"name":"Khuchtumur Bum‐Erdene","orcid":"0000-0003-3222-7384","position":6,"is_corresponding":false},{"id":499599,"name":"I. Darren Grice","orcid":"0000-0001-9218-457X","position":7,"is_corresponding":false},{"id":308669,"name":"Mark von Itzstein","orcid":"0000-0001-6302-7524","position":8,"is_corresponding":false},{"id":754586,"name":"Helen Blanchard","orcid":"0000-0003-3372-5027","position":9,"is_corresponding":false},{"id":249841,"name":"Nora Heisterkamp","orcid":"0000-0003-2769-2273","position":10,"is_corresponding":false},{"id":754584,"name":"Somayeh S. Tarighat","orcid":"0000-0003-4369-9352","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:49:26.966524Z","pmid":"34830047","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}