{"doi":"10.1101/2023.03.13.532152","title":"Targeted engagement of β-catenin-Ikaros complexes in refractory B-cell malignancies","abstract":"ABSTRACT In most cell types, nuclear β-catenin functions as prominent oncogenic driver and pairs with TCF7-family factors for transcriptional activation of MYC. Surprisingly, B-lymphoid malignancies not only lacked expression and activating lesions of β-catenin but critically depended on GSK3β for effective β-catenin degradation. Our interactome studies in B-lymphoid tumors revealed that β-catenin formed repressive complexes with lymphoid-specific Ikaros factors at the expense of TCF7. Instead of MYC-activation, β-catenin was essential to enable Ikaros-mediated recruitment of nucleosome remodeling and deacetylation (NuRD) complexes for transcriptional repression of MYC. To leverage this previously unrecognized vulnerability of B-cell-specific repressive β-catenin-Ikaros-complexes in refractory B-cell malignancies, we examined GSK3β small molecule inhibitors to subvert β-catenin degradation. Clinically approved GSK3β-inhibitors that achieved favorable safety prof les at micromolar concentrations in clinical trials for neurological disorders and solid tumors were effective at low nanomolar concentrations in B-cell malignancies, induced massive accumulation of β-catenin, repression of MYC and acute cell death. Preclinical in vivo treatment experiments in patient-derived xenografts validated small molecule GSK3β-inhibitors for targeted engagement of lymphoid-specific β-catenin-Ikaros complexes as a novel strategy to overcome conventional mechanisms of drug-resistance in refractory malignancies. HIGHLIGHTS Unlike other cell lineages, B-cells express nuclear β-catenin protein at low baseline levels and depend on GSK3β for its degradation. In B-cells, β-catenin forms unique complexes with lymphoid-specific Ikaros factors and is required for Ikaros-mediated tumor suppression and assembly of repressive NuRD complexes. CRISPR-based knockin mutation of a single Ikaros-binding motif in a lymphoid MYC superenhancer region reversed β-catenin-dependent Myc repression and induction of cell death. The discovery of GSK3β-dependent degradation of β-catenin as unique B-lymphoid vulnerability provides a rationale to repurpose clinically approved GSK3β-inhibitors for the treatment of refractory B-cell malignancies. GRAPHICAL ABSTRACT Abundant nuclear β-catenin β-catenin pairs with TCF7 factors for transcriptional activation of MYC B-cells rely on efficient degradation of β-catenin by GSK3β B-cell-specific expression of Ikaros factors Unique vulnerability in B-cell tumors: GSK3β-inhibitors induce nuclear accumulation of β-catenin. β-catenin pairs with B-cell-specific Ikaros factors for transcriptional repression of MYC","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":398746,"datarank":0.11530236753545245,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.011330290451460643,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.011330290451460643,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.943,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1174998,"name":"Huda Jumaa","orcid":null,"position":1,"is_corresponding":false},{"id":272473,"name":"Mark E. 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Davids","orcid":"0000-0003-4529-2003","position":19,"is_corresponding":false},{"id":720731,"name":"Hilde Schjerven","orcid":"0000-0001-9287-3375","position":20,"is_corresponding":false},{"id":1174775,"name":"Julia Jellusova","orcid":"0000-0002-5234-2104","position":21,"is_corresponding":false},{"id":108573,"name":"Markus Müschen","orcid":"0000-0002-6064-8613","position":22,"is_corresponding":false},{"id":272481,"name":"Kadriye Nehir Cosgun","orcid":"0000-0003-4181-744X","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:19:47.744358Z","pmid":"36993619","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":[]}