Introduction: Myeloproliferative neoplasms (MPNs) are clonal hematological disorders characterized by the abnormal proliferation of one or more blood cell lineages. The three classical subtypes include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The discovery of the JAK2V617F mutation in 2005 was a landmark event in the understanding of MPN biology, but subsequent research has demonstrated that this single alteration does not fully account for the complexity and clinical diversity of these disorders.
Additional somatic mutations have been identified in recent years, many of which affect genes involved in epigenetic regulation. Among them, the ASXL1 (Additional sex combs-like 1) gene, located on chromosome 20q, has emerged as one of the most clinically significant. The protein encoded by ASXL1 contributes to chromatin remodeling and gene expression control. Loss-of-function mutations, most commonly nonsense or frameshift variants in exon 12, disrupt these regulatory mechanisms, leading to transcriptional deregulation and altered hematopoietic differentiation.
Multiple studies have indicated that ASXL1 mutations are associated with worse clinical outcomes, including progressive marrow fibrosis, severe symptom burden, reduced overall survival, and increased risk of leukemic transformation to acute myeloid leukemia (AML). Given these observations, ASXL1 is increasingly considered an important biomarker for disease prognosis and risk stratification in patients with MPNs
Methods: A systematic literature review was performed to evaluate the prevalence and prognostic implications of ASXL1 mutations in MPNs. Searches were conducted in PubMed, Scopus, and Web of Science databases for studies published between January 2010 and December 2024. The following keywords were applied: ASXL1 mutation, myeloproliferative neoplasms, JAK2, prognosis, epigenetic regulators.
Inclusion criteria: original research articles that examined ASXL1 mutations in patients with MPNs and reported their association with clinical outcomes, survival, or disease progression.
Exclusion criteria: studies focusing exclusively on other mutations, review articles, case reports, and those without full-text access.
Data were extracted regarding mutation frequency, mutation type, and reported clinical consequence
Results: The review identified multiple studies confirming the clinical relevance of ASXL1 mutations in MPNs. These mutations represent one of the most frequent secondary genetic alterations and are often found in combination with JAK2V617F.
Prevalence: The frequency of ASXL1 mutations varies across subtypes, ranging from 5–15% in PV and ET to 20–35% in PMF. This distribution suggests a stronger pathogenic role in fibrotic progression.
Molecular features: Most mutations occur in exon 12 and are nonsense or frameshift variants, leading to truncated, non-functional proteins. The resulting loss of function disrupts chromatin-modifying complexes such as PRC2, altering transcriptional programs involved in hematopoietic stem cell differentiation and promoting leukemogenesis.
Clinical associations: Patel et al. (2018) reported that ASXL1 mutations were associated with more severe symptoms, such as splenomegaly and marrow failure, and shorter survival in MPN patients. Guglielmelli et al. (2019) found that ASXL1 was an independent predictor of AML transformation in PMF. Cabagnols et al. (2020) demonstrated that PV and ET patients with ASXL1 mutations had a higher risk of secondary myelofibrosis and reduced event-free survival. Grinfeld et al. (2022) showed that co-occurrence of ASXL1 with other epigenetic mutations worsened prognosis. Rampal et al. (2023) confirmed that ASXL1 is one of the strongest predictors of AML transformation and poor overall survival in PMF.
Table 1. Selected studies on ASXL1 mutations in MPNs
Author & Year Population Disease Type Frequency Clinical Outcome
Patel et al., 2018 500 JAK2+ patients MPN 15% Severe symptoms, reduced survival
Guglielmelli et al., 2019 460 patients PMF 30% Higher risk of AML transformation
Cabagnols et al., 2020 200 patients PV, ET 8–12% Increased risk of secondary fibrosis
Grinfeld et al., 2022 2000 patients MPN (genomic) 10–20% Worse prognosis with co-mutations
Rampal et al., 2023 International cohort PMF 20–35% Strong predictor of AML and shorter survival
Conclusion: ASXL1 mutations are among the most clinically significant genetic alterations in MPNs. Their prevalence is relatively low in PV and ET but considerably higher in PMF, where they play a critical role in disease progression. Evidence consistently links these mutations to severe symptoms, progressive fibrosis, reduced survival, and increased risk of leukemic transformation.
Incorporating ASXL1 mutation status into prognostic models can enhance patient risk stratification and guide treatment strategies. Routine evaluation of ASXL1 should be considered in clinical practice to identify high-risk patients. Future large-scale studies across diverse populations are necessary to validate its prognostic role and explore its potential as a therapeutic target.