{"doi":"10.1101/2020.03.12.989277","title":"Lgr5-mediated restraint of β-catenin is essential for B-lymphopoiesis and leukemia-initiation","abstract":"Upon productive immunoglobulin gene rearrangement, expression of a functional pre-B cell receptor (pre-BCR) initiates positive selection of pre-B cells, clonal expansion and self-renewal 1-2 . Studying mechanisms driving this first wave of B-lymphopoiesis, we identified the G-protein coupled receptor Lgr5 as an essential initiator of positive selection. Lgr5 was extensively studied as determinant of stem cell populations in multiple tissues 3-6 , but not in B-cells. While undetectable throughout the hematopoietic system, positively selected pre-B cells were marked with a sharp peak of Lgr5 expression. Conditional deletion of Lgr5 preceding the pre-BCR checkpoint induced negative selection and complete abortion of B-cell development. Proteomic studies of Lgr5 -ablation revealed massive (>250-fold) accumulation of β-catenin and suppression of MYC. Lgr5 -deficient pre-B cells fully recovered by concurrent β-catenin-deletion, demonstrating a central role of Lgr5-mediated restraint of β-catenin at the pre-BCR checkpoint. In other cell types, β-catenin/TCF4 complexes drive transcriptional activation of MYC 7-9 . Instead of TCF4, proximity-based interactome studies in pre-B cells identified the B-lymphoid transcription factors IKZF1 and IKZF3 10-11 as β-catenin-binding partners, which had the opposite effect and caused transcriptional repression of MYC . On positively selected pre-B cells, Lgr5 prevented accumulation of β-catenin and formation of complexes with IKZF1 and IKZF3, which relieved transcriptional repression of MYC. Activating β-catenin-mutations are common throughout all main types of cancer 7-8 , but were conspicuously absent in pre-B leukemia (B-ALL). Like pre-B cells, B-ALL cells were uniquely sensitive to genetic and pharmacological β-catenin hyperactivation, which recapitulated the effects of Lgr5 -deletion and compromised colony formation and leukemia-initiation. A new LGR5 antibody-drug conjugate targeted leukemia-initiating cells in patient-derived B-ALL and achieved long-term disease-control. Likewise, small molecule hyperactivation of β-catenin selectively killed B-ALL but not other cell types. Hence, Lgr5-mediated restraint of β-catenin activation is essential for B-lymphopoiesis and revealed an unexpected vulnerability that can be leveraged for the treatment of drug-resistant B-ALL.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":124707,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":272473,"name":"Mark E. 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Chan","orcid":null,"position":7,"is_corresponding":false},{"id":272483,"name":"Kohei Kume","orcid":"0000-0003-2856-5970","position":8,"is_corresponding":false},{"id":569885,"name":"Maurizio Mangolini","orcid":"0000-0002-0074-7935","position":9,"is_corresponding":false},{"id":272480,"name":"Janet Winchester","orcid":"0000-0002-8521-9153","position":10,"is_corresponding":false},{"id":362257,"name":"Zhengshan Chen","orcid":"0000-0003-2869-1467","position":11,"is_corresponding":false},{"id":569886,"name":"Lu Yang","orcid":"0000-0003-2176-7684","position":12,"is_corresponding":false},{"id":272482,"name":"Huimin Geng","orcid":"0000-0001-5339-5446","position":13,"is_corresponding":false},{"id":569887,"name":"Shai Izraeli","orcid":"0000-0002-6938-2540","position":14,"is_corresponding":false},{"id":423661,"name":"Joo Y. Song","orcid":"0000-0003-3497-2513","position":15,"is_corresponding":false},{"id":379085,"name":"Wing C. Chan","orcid":"0000-0002-6243-6008","position":16,"is_corresponding":false},{"id":569888,"name":"Andrew G. Polson","orcid":"0000-0003-3289-6502","position":17,"is_corresponding":false},{"id":362264,"name":"Hassan Jumaa","orcid":"0000-0003-3383-141X","position":18,"is_corresponding":false},{"id":3646,"name":"Hans Clevers","orcid":"0000-0002-3077-5582","position":19,"is_corresponding":false},{"id":108573,"name":"Markus Müschen","orcid":"0000-0002-6064-8613","position":20,"is_corresponding":false},{"id":272481,"name":"Kadriye Nehir Cosgun","orcid":"0000-0003-4181-744X","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-18T23:15:11.632153Z","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":[]}