{"doi":"10.1101/2021.09.24.461149","title":"Overcoming microenvironment-mediated chemoprotection through stromal galectin-3 inhibition in acute lymphoblastic leukemia","abstract":"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, 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, induction of apoptosis and, importantly, 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":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":216131,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9527,"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":48,"raw_metadata":null,"created_at":"2026-07-18T23:53:00.192353Z","pmid":null,"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":[]}