{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Kohnke T"],"funding":["Deutsche Forschungsgemeinschaft","Paul G. Allen Frontiers Group","NHLBI NIH HHS","National Heart, Lung, and Blood Institute","Mark Foundation For Cancer Research","National Cancer Institute","NCI NIH HHS","American Society of Hematology","Edward P. Evans Foundation","Leukemia and Lymphoma Society"],"pagination":["202-223"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11061584"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["5(3)"],"pubmed_abstract":["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 H2"],"journal":["Blood cancer discovery"],"pubmed_title":["Human ASXL1-Mutant Hematopoiesis Is Driven by a Truncated Protein Associated with Aberrant Deubiquitination of H2AK119."],"pmcid":["PMC11061584"],"funding_grant_id":["1R01HL142637","3406-21","R01 CA251331","KO 5509/1-1","R01 HL142637","1R01CA251331","T32 CA009302","Research Restart Award"],"pubmed_authors":["Nuno KA","Gars EJ","Fan AC","Majeti R","Kohnke T","Alder CC","Phan P"],"additional_accession":[]},"is_claimable":false,"name":"Human ASXL1-Mutant Hematopoiesis Is Driven by a Truncated Protein Associated with Aberrant Deubiquitination of H2AK119.","description":"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 H2","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 May","modification":"2026-07-15T04:01:17.821Z","creation":"2025-04-04T00:26:32.812Z"},"accession":"S-EPMC11061584","cross_references":{"pubmed":["38359087"],"doi":["10.1158/2643-3230.BCD-23-0235"]}}