{"doi":"10.1126/science.adx4174","title":"Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation","abstract":"<jats:p>\n                    Somatic mutations that increase the fitness of hematopoietic stem cells (HSCs) drive their expansion in clonal hematopoiesis (CH) and predispose individuals to blood cancers. Population variation in the growth rate and potential of mutant clones suggests that genetic factors may confer resilience against CH. Here, we identified a noncoding regulatory variant, rs17834140-T, that protects against CH and myeloid malignancies by selectively down-regulating the RNA-binding protein MSI2 in HSCs. By modeling variant effects and mapping MSI2 binding targets, we uncovered an RNA network that maintains human HSCs and influences CH risk. Variant rs17834140-T was associated with slower CH expansion, and stem cell MSI2 levels modified\n                    <jats:italic toggle=\"yes\">ASXL1</jats:italic>\n                    -mutant HSC clonal dominance. These findings leverage natural resilience to illuminate posttranscriptional regulation in human HSCs, suggesting that inhibition of MSI2 or its targets could be rational strategies for blood cancer prevention.\n                  </jats:p>","journal":"Science","year":2026,"id":595681,"datarank":0.31191623125197543,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"self_citation_contribution":0.31191623125197543,"citation_network_contribution":0.0,"self_endowment_contribution":0.31191623125197543,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":17317,"name":"Mateusz Antoszewski","orcid":"0000-0002-7651-0547","position":1,"is_corresponding":false},{"id":1525446,"name":"Xueqin Xie","orcid":null,"position":2,"is_corresponding":false},{"id":641922,"name":"Yash Pershad","orcid":"0000-0002-2282-1403","position":3,"is_corresponding":false},{"id":1096749,"name":"Uma P. Arora","orcid":"0000-0002-3598-5386","position":4,"is_corresponding":false},{"id":993485,"name":"Chi-Lam Poon","orcid":"0000-0001-6298-7099","position":5,"is_corresponding":false},{"id":1162799,"name":"Peng Lyu","orcid":"0000-0003-3281-7560","position":6,"is_corresponding":false},{"id":1183309,"name":"Andrew Lee","orcid":"0000-0001-9917-8834","position":7,"is_corresponding":false},{"id":1162797,"name":"Chun-Jie Guo","orcid":null,"position":8,"is_corresponding":false},{"id":1376049,"name":"Tianyi Ye","orcid":"0000-0002-8242-5242","position":9,"is_corresponding":false},{"id":1525452,"name":"Laila Barakat Norford","orcid":"0009-0006-9224-3625","position":10,"is_corresponding":false},{"id":104481,"name":"Anna‐Lena Neehus","orcid":"0000-0002-8573-6820","position":11,"is_corresponding":false},{"id":1376047,"name":"Lucrezia della Volpe","orcid":"0000-0002-9087-1293","position":12,"is_corresponding":false},{"id":17321,"name":"Lara Wahlster","orcid":"0000-0001-8409-7580","position":13,"is_corresponding":false},{"id":1253760,"name":"D.M.S.H.K. Ranasinghe","orcid":"0000-0001-5151-8908","position":14,"is_corresponding":false},{"id":298389,"name":"Tzu‐Chieh Ho","orcid":"0000-0002-2913-9319","position":15,"is_corresponding":false},{"id":1122588,"name":"Trevor Barlowe","orcid":"0009-0002-1507-3539","position":16,"is_corresponding":false},{"id":252079,"name":"Arthur Chow","orcid":"0000-0003-4922-0410","position":17,"is_corresponding":false},{"id":292724,"name":"Alexandra Schurer","orcid":"0000-0001-8028-838X","position":18,"is_corresponding":false},{"id":273672,"name":"James Taggart","orcid":"0000-0002-6853-1583","position":19,"is_corresponding":false},{"id":297431,"name":"Benjamin H. Durham","orcid":"0000-0001-8090-5448","position":20,"is_corresponding":false},{"id":75043,"name":"Omar Abdel-Wahab","orcid":"0000-0002-3907-6171","position":21,"is_corresponding":false},{"id":356131,"name":"Kathy L. McGraw","orcid":"0000-0001-9184-5399","position":22,"is_corresponding":false},{"id":613858,"name":"James M. Allan","orcid":"0000-0002-7580-5087","position":23,"is_corresponding":false},{"id":74618,"name":"Ruslan Soldatov","orcid":"0000-0002-5670-5881","position":24,"is_corresponding":false},{"id":27378,"name":"Alexander G. Bick","orcid":"0000-0001-5824-9595","position":25,"is_corresponding":false},{"id":292725,"name":"Michael G. Kharas","orcid":"0000-0002-1165-6991","position":26,"is_corresponding":false},{"id":17323,"name":"Vijay G. Sankaran","orcid":"0000-0003-0044-443X","position":27,"is_corresponding":false},{"id":951304,"name":"Gaurav Agarwal","orcid":"0000-0003-4194-2670","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation","abstract":"<jats:p>\n                    Somatic mutations that increase the fitness of hematopoietic stem cells (HSCs) drive their expansion in clonal hematopoiesis (CH) and predispose individuals to blood cancers. Population variation in the growth rate and potential of mutant clones suggests that genetic factors may confer resilience against CH. Here, we identified a noncoding regulatory variant, rs17834140-T, that protects against CH and myeloid malignancies by selectively down-regulating the RNA-binding protein MSI2 in HSCs. By modeling variant effects and mapping MSI2 binding targets, we uncovered an RNA network that maintains human HSCs and influences CH risk. Variant rs17834140-T was associated with slower CH expansion, and stem cell MSI2 levels modified\n                    <jats:italic toggle=\"yes\">ASXL1</jats:italic>\n                    -mutant HSC clonal dominance. These findings leverage natural resilience to illuminate posttranscriptional regulation in human HSCs, suggesting that inhibition of MSI2 or its targets could be rational strategies for blood cancer prevention.\n                  </jats:p>","is_dataset_classified":null,"base_score":1.791759469228055,"endowment":1.791759469228055,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41477881","pmcid":null,"openalex_id":"https://openalex.org/W7117885814","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"R01 DK103794","title":null},{"funder_name":"National Institutes of Health","grant_id":"R01 CA265726","title":null},{"funder_name":"National Institutes of Health","grant_id":"R01 CA292941","title":null},{"funder_name":"National Institutes of Health","grant_id":"R33 CA278393","title":null},{"funder_name":"National Institutes of Health","grant_id":"R01 HL146500","title":null},{"funder_name":"Howard Hughes Medical Institute","grant_id":"Investigator Award","title":null},{"funder_name":"NIH HHS","grant_id":"DP5 OD029586","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P30 CA008748","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA193842","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA283578","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA225231","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"U54 DK106829","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA274249","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA186702","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"R01 DK101989","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"K01 DK084261","title":null},{"funder_name":"NIA NIH HHS","grant_id":"R01 AG088657","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL135564","title":null},{"funder_name":"NIA NIH HHS","grant_id":"R01 AG083736","title":null},{"funder_name":"Howard Hughes Medical Institute","grant_id":"","title":null}],"total_grants":20,"fwci":40.9904,"citation_percentile":0.9983891,"influential_citations":0,"citation_trend":[{"year":2026,"count":5}],"oa_status":"green","license":null,"oa_locations":[{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12850507/","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12850507/","host_type":"repository"},{"url":"https://www.science.org/doi/pdf/10.1126/science.adx4174","host_type":"publisher"},{"url":"https://doi.org/10.1126/science.adx4174","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41477881","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12850507","host_type":"repository"}],"fields_of_study":["Acute Myeloid Leukemia Research","Single-cell and spatial transcriptomics","Hematopoietic Stem Cell Transplantation","Humans","Clonal Hematopoiesis","Down-Regulation","Hematologic Neoplasms","Hematopoietic Stem Cells","Mutation","Repressor Proteins","RNA-Binding Proteins"],"mesh_terms":["Clonal Hematopoiesis","Hematopoiesis","Hematopoietic Stem Cells","Humans","Mutation","Repressor Proteins","Down-Regulation","RNA-Binding Proteins","Hematologic Neoplasms"],"keywords":["Haematopoiesis","Stem cell","Somatic cell","Population","Mutant","Myeloid","RNA","Hematopoietic stem cell"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-27T17:46:44.406608Z","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":[]}