ASXL1 Mutations Are Associated with Immune Dysregulation and High-Risk Clinical Features on Ethiopian Chronic Myeloid Leukemia Cohort

Background: Additional Sex Combs-Like 1 (ASXL1) mutations are recurrent adverse prognostic events in myeloid malignancies and are linked to epigenetic dysregulation and inflammatory signaling. However, their clinical and immunologic impact in chronic myeloid leukemia (CML), particularly in sub-Saharan African populations with a chronically heightened inflammatory baseline, remains poorly characterized.<br><br>Methods: We conducted a cross-sectional retrospective study of 24 cytogenetically confirmed Philadelphia chromosome–positive (Ph+) CML patients from Ethiopia. Targeted sequencing was used to assess the Clonal Hematopoiesis (CH)–associated genes DNMT3A, TET2, ASXL1, and JAK2. Peripheral blood immunophenotyping was performed by multiparameter flow cytometry, and plasma cytokine levels were quantified using a multiplex Luminex assay. Prognostic risk at diagnosis was assessed using the Sokal score. <br><br>Findings: ASXL1 mutation variants (Tier I–II) were identified in 29.2% (7/24) of patients, with no mutations detected in the other CH genes tested. During follow-up, ASXL1-mutant patients exhibited BCR::ABL1 transcript levels significantly higher than those of patients with wild-type ASXL1 (median 55.8% vs. 13.3% IS; P = 0.033), indicating inferior molecular response. ASXL1-mutant cases showed relative enrichment of immature hematopoietic populations. Cytokine profiling revealed a predominantly pro-inflammatory milieu, marked by significant elevations in IL-18 (p=0.01) and MCP-1 (p=0.03), alongside a concurrent increase in the immunomodulatory cytokine IL-27 (p=0.01).<br><br>Interpretation: CML Patients with ASXL1 mutations exhibited high-risk clinical features and evidence of immune dysregulation skewed toward a pro-inflammatory profile. This inflammatory immune remodeling may impair effective antitumor immunity, a key determinant of clinical outcomes in CML. Larger longitudinal studies in underrepresented populations are warranted to confirm these findings.