Research Article: Prognostic heterogeneity in ASXL1-mutated AML and refinement by an immunophenotype-based score
Abstract:
ASXL1 is a frequently mutated gene in acute myeloid leukemia (AML) and is clinically recognized as an adverse prognostic marker, yet its clinical impact remains markedly heterogeneous.
Utilizing the BeatAML cohort, we integrated genomic, transcriptomic, immunophenotypic, and drug-sensitivity data to delineate this variability.
Although ASXL1 mutations remained an independent adverse factor in multivariable analyses, survival outcomes did not differ significantly between ASXL1 -mutated patients and those lacking other high-risk lesions after excluding co-occurring adverse mutations, suggesting that ASXL1 status alone does not uniformly dictate prognosis. By stratifying ASXL1 -mutated patients based on treatment response, we identified two biologically distinct subsets-complete remission (CR) versus relapsed/refractory (R/R)-characterized by divergent clinical outcomes. Comparative analyses revealed distinct transcriptional profiles, including upregulated MAP3K15 expression in ASXL1 -mutated cases, alongside consistent immunophenotypic downregulation of CD11b, CD123, and HLA-DR in R/R patients. Leveraging these routinely measured markers, we developed a three-parameter ImmuScore that robustly stratified prognosis in both the BeatAML cohort and an independent clinical validation set. Importantly, the ImmuScore captured functional drug-response patterns: patients with low scores displayed significantly higher Z-scores-indicating reduced sensitivity across multiple chemotherapeutic and targeted agents.
These findings link immunophenotypic signatures to therapeutic vulnerability, providing a mechanistic explanation for treatment failure in a subset of ASXL1 -mutated AML. To address potential small-sample bias, Firth penalized regression was applied. Collectively, this study demonstrates that ASXL1 -mutated AML is not a monolithic high-risk entity. The ImmuScore provides a biologically informed and clinically feasible tool to identify truly high-risk ASXL1 -mutated patients, potentially guiding personalized therapeutic strategies.
Introduction:
ASXL1 is a frequently mutated gene in acute myeloid leukemia (AML) and is clinically recognized as an adverse prognostic marker, yet its clinical impact remains markedly heterogeneous.
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