ASXL1 mutation-related clonal hematopoiesis and age-related diseases: clinical evidence and molecular insights

Abstract

Clonal hematopoiesis (CH) is defined as the age-associated expansion of hematopoietic stem and progenitor cells harboring somatic mutations, most frequently in epigenetic regulators such as DNMT3A, TET2, and ASXL1. Although CH was initially recognized as a precursor to hematological malignancies, accumulating evidence has led to its broad recognition as a relevant factor in various age-related nonmalignant diseases, particularly those with inflammatory components, such as cardiovascular disease, autoimmune disorders, and solid tumors. Notably, the increased overall mortality associated with CH is primarily driven by cardiovascular complications rather than hematological malignancies. Among CH-associated genes, ASXL1 mutations are distinguished by their strong associations with adverse clinical outcomes and pro-inflammatory signatures. However, compared to TET2 and DNMT3A, the molecular and pathological implications of ASXL1-mutated CH remain underexplored. Recent studies have expanded the disease spectrum of ASXL1 mutations beyond hematological malignancies, implicating them in clonal expansion and systemic inflammation. This review aims to summarize the current epidemiological and experimental insights into ASXL1-mutated CH, focusing on its potential contributions to inflammation-associated diseases. By integrating clinical observations and emerging mechanistic data, we highlight the urgent need for deeper investigation into ASXL1-driven CH and its systemic consequences beyond hematological transformation.

Keywords: ASXL1; autoimmune disease; chronic inflammation,; clonal hematopoiesis.

Fig. 1

Localization of ASXL1 mutations in individuals with CH modified from a previous study by Vlasschaert et al. with the UK biobank cohort [41]. Nonsense or frameshift mutations in the ASXL1 gene are concentrated in the N-terminus of the last exon (gray colored), generating a C-terminally truncated form of ASXL1 (Mutant ASXL1). Hotspot mutations are indicated in boldface. ASXH = Asx homology; ASXN = Asx N-terminal; GRR = Glycine-rich region NR box = nuclear receptor co-regulator binding motif; PHD = plant homeodomain

Fig. 2

Summary of reported correlations between ASXL1-CH and various conditions, including cardiovascular disease, infection, cancers, and autoimmune disorders. All listed conditions share chronic inflammation as a unifying pathological background, potentially mediated by ASXL1-CH. CH clonal hematopoiesis, HIV human immunodeficiency virus. Created in BioRender. Sato, N. (2025) https://BioRender.com/fai2raa

Fig. 3

Schematic representation of the interacting proteins of wild-type ASXL1 and C-terminally truncated mutant ASXL1. The ASXL1-interacting proteins newly identified are red colored. NLS = nuclear localization signal; LLPS = liquid-liquid phase separation; DEUBAD = deubiquitinase adaptor domain; IDR = intrinsically disordered regions