A mutant ASXL1-BAP1-EHMT complex contributes to heterochromatin dysfunction in clonal hematopoiesis and chronic monomyelocytic leukemia

• DOI: 10.1073/pnas.2413302121
• Publication Date: 2025-01-03T18:52:12Z
• Authors: Zhen Dong; Hugo Sepulveda; Leo J. Arteaga-Va...; Chad Blouin; Jenna Fernandez; Moritz Binder; Wen-Chien Chou; Hwei-Fang Tien; Mrinal M. Patnaik; Geoffrey J. Faulkner; Samuel A. Myers; Anjana Rao
• Keywords: Constitutive heterochromatin

ASXL transcriptional regulator 1 (ASXL1) is one of the three most frequently mutated genes in age-related clonal hematopoiesis (CH), alongside DNA methyltransferase 3 alpha (DNMT3A) and Tet methylcytosine dioxygenase 2 ( TET2) . CH can progress to myeloid malignancies including chronic monomyelocytic leukemia (CMML) also strongly associated with inflammatory cardiovascular disease all-cause mortality humans. DNMT3A TET2 regulate methylation demethylation pathways, respectively, loss-of-function mutations these reduce heterochromatin, allowing derepression silenced elements heterochromatin. In contrast, mechanisms that connect mutant ASXL1 are not yet fully understood. CH/CMML-associated encode C-terminally truncated proteins enhance deubiquitinase activity ASXL-BAP1 “PR-DUB” complex, which removes monoubiquitin from H2AK119Ub. Here, we show interact euchromatic histone lysine methyltransferases (EHMT1–EHMT2) generates H3K9me1 me2, latter a repressive modification constitutive Compared cells age-matched wild-type mice, found expanded old (≥18-mo-old) Asxl1tm/+ heterozygous knock-in mouse model CH, display genome-wide decreases H3K9me2, H3K9me3, H2AK119Ub as well an increase expression transposable (TEs) satellite repeats. Increased TE was observed monocytes -mutant CMML patients compared healthy controls. Our data suggest compromise integrity both facultative heterochromatin age-dependent manner by reducing levels H3K9me2/3 This correlated increased nearby genes, many interferon-inducible (inflammation-associated) (ISGs).