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Prognostic heterogeneity in ASXL1-mutated AML and refinement by an immunophenotype-based score
Yaming Zhang1, Min Zhang2, Yali Huang1
1Department of Hematology, Key Laboratory of Hematological Malignancies at Affiliated Hospital of Guizhou Medical University, Guiyang, China.
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.
Methods:
Utilizing the BeatAML cohort, we integrated genomic, transcriptomic, immunophenotypic, and drug-sensitivity data to delineate this variability.
Results:
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.
Discussion:
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.
