biostudies-literatureKohnke TDeutsche ForschungsgemeinschaftPaul G. Allen Frontiers GroupNHLBI NIH HHSNational Heart, Lung, and Blood InstituteMark Foundation For Cancer ResearchNational Cancer InstituteNCI NIH HHSAmerican Society of HematologyEdward P. Evans FoundationLeukemia and Lymphoma Society202-223https://www.ebi.ac.uk/biostudies/studies/S-EPMC11061584biostudies-literatureUnknown5(3)Mutations in additional sex combs like 1 (ASXL1) confer poor prognosis both in myeloid malignancies and in premalignant clonal hematopoiesis (CH). However, the mechanisms by which these mutations contribute to disease initiation remain unresolved, and mutation-specific targeting has remained elusive. To address this, we developed a human disease model that recapitulates the disease trajectory from ASXL1-mutant CH to lethal myeloid malignancy. We demonstrate that mutations in ASXL1 lead to the expression of a functional, truncated protein and determine that truncated ASXL1 leads to global redistribution of the repressive chromatin mark H2AK119Ub, increased transposase-accessible chromatin, and activation of both myeloid and stem cell gene-expression programs. Finally, we demonstrate that H2Blood cancer discoveryHuman ASXL1-Mutant Hematopoiesis Is Driven by a Truncated Protein Associated with Aberrant Deubiquitination of H2AK119.PMC110615841R01HL1426373406-21R01 CA251331KO 5509/1-1R01 HL1426371R01CA251331T32 CA009302Research Restart AwardNuno KAGars EJFan ACMajeti RKohnke TAlder CCPhan PfalseHuman ASXL1-Mutant Hematopoiesis Is Driven by a Truncated Protein Associated with Aberrant Deubiquitination of H2AK119.Mutations in additional sex combs like 1 (ASXL1) confer poor prognosis both in myeloid malignancies and in premalignant clonal hematopoiesis (CH). However, the mechanisms by which these mutations contribute to disease initiation remain unresolved, and mutation-specific targeting has remained elusive. To address this, we developed a human disease model that recapitulates the disease trajectory from ASXL1-mutant CH to lethal myeloid malignancy. We demonstrate that mutations in ASXL1 lead to the expression of a functional, truncated protein and determine that truncated ASXL1 leads to global redistribution of the repressive chromatin mark H2AK119Ub, increased transposase-accessible chromatin, and activation of both myeloid and stem cell gene-expression programs. Finally, we demonstrate that H22024-01-01T00:00:00Z2024 May2026-07-15T04:01:17.821Z2025-04-04T00:26:32.812ZS-EPMC110615843835908710.1158/2643-3230.BCD-23-0235