{"doi":"10.1016/j.cell.2023.12.016","title":"Inherited blood cancer predisposition through altered transcription elongation","abstract":"Despite advances in defining diverse somatic mutations that cause myeloid malignancies, a significant heritable component for these cancers remains largely unexplained. Here, we perform rare variant association studies in a large population cohort to identify inherited predisposition genes for these blood cancers. CTR9, which encodes a key component of the PAF1 transcription elongation complex, is among the significant genes identified. The risk variants found in the cases cause loss of function and result in a ∼10-fold increased odds of acquiring a myeloid malignancy. Partial CTR9 loss of function expands human hematopoietic stem cells (HSCs) by increased super elongation complex-mediated transcriptional activity, which thereby increases the expression of key regulators of HSC self-renewal. By following up on insights from a human genetic study examining inherited predisposition to the myeloid malignancies, we define a previously unknown antagonistic interaction between the PAF1 and super elongation complexes. These insights could enable targeted approaches for blood cancer prevention.","journal":"Cell","year":2024,"id":422784,"datarank":0.6937495244727522,"base_score":3.258096538021482,"endowment":3.258096538021482,"self_citation_contribution":0.4887144807032224,"citation_network_contribution":0.2050350437695298,"self_endowment_contribution":0.4887144807032224,"citer_contribution":0.2050350437695298,"corpus_percentile":null,"corpus_rank":null,"citation_count":25,"citer_count":17,"citers_with_citation_signal":12,"citers_with_endowment":12,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9523,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE186591"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":17314,"name":"Liam D. Cato","orcid":"0000-0003-1578-3477","position":1,"is_corresponding":false},{"id":1096749,"name":"Uma P. Arora","orcid":"0000-0002-3598-5386","position":2,"is_corresponding":false},{"id":27377,"name":"Erik L. Bao","orcid":"0000-0002-6074-6766","position":3,"is_corresponding":false},{"id":989287,"name":"Samuel C. Bryant","orcid":"0009-0001-9891-0488","position":4,"is_corresponding":false},{"id":839806,"name":"Nicholas Williams","orcid":"0000-0003-3989-9167","position":5,"is_corresponding":false},{"id":323318,"name":"Yuemeng Jia","orcid":"0000-0002-8019-1534","position":6,"is_corresponding":false},{"id":649820,"name":"Seth Goldman","orcid":"0000-0001-5096-3778","position":7,"is_corresponding":false},{"id":613027,"name":"Jyoti Nangalia","orcid":"0000-0001-7122-4608","position":8,"is_corresponding":false},{"id":116744,"name":"Michael A. Erb","orcid":"0000-0001-9993-3481","position":9,"is_corresponding":false},{"id":58317,"name":"Seychelle M. Vos","orcid":"0000-0003-1985-2994","position":10,"is_corresponding":false},{"id":236907,"name":"Scott A. Armstrong","orcid":"0000-0002-9099-4728","position":11,"is_corresponding":false},{"id":17323,"name":"Vijay G. Sankaran","orcid":"0000-0003-0044-443X","position":12,"is_corresponding":false},{"id":363391,"name":"Jiawei Zhao","orcid":"0000-0003-0682-4601","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T01:57:51.642883Z","pmid":"38218188","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":[]}