biostudies-literatureZhao JNew York Stem Cell FoundationCancer Research UKAlex's Lemonade Stand Foundation for Childhood CancerNIDDK NIH HHSHoward Hughes Medical InstituteMPN Research FoundationNHLBI NIH HHSMedical Research CouncilNCI NIH HHSNational Institutes of HealthEdward P. Evans FoundationLeukemia and Lymphoma Society642-658.e19https://www.ebi.ac.uk/biostudies/studies/S-EPMC10872907biostudies-literatureUnknown187(3)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-renewaCellInherited blood cancer predisposition through altered transcription elongation.PMC10872907R01 DK103794P01 CA066996R01 HL146500RCCASF-May22\100002T32 HL007574MC_PC_17230R01 CA265726Arora UPCato LDWilliams NNangalia JSankaran VGGoldman SRErb MAArmstrong SAVos SMBryant SCJia YZhao JBao ELfalseInherited blood cancer predisposition through altered transcription elongation.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-renewa2024-01-01T00:00:00Z2024 Feb2026-06-02T11:57:35.241Z2025-04-03T23:23:42.34ZS-EPMC108729073821818810.1016/j.cell.2023.12.016