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Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      <jats:italic>ASXL1<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Utilizing the BeatAML cohort, we integrated genomic, transcriptomic, immunophenotypic, and drug-sensitivity data to delineate this variability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Although\n                      <jats:italic>ASXL1<\/jats:italic>\n                      mutations remained an independent adverse factor in multivariable analyses, survival outcomes did not differ significantly between\n                      <jats:italic>ASXL1<\/jats:italic>\n                      -mutated patients and those lacking other high-risk lesions after excluding co-occurring adverse mutations, suggesting that\n                      <jats:italic>ASXL1<\/jats:italic>\n                      status alone does not uniformly dictate prognosis. By stratifying\n                      <jats:italic>ASXL1<\/jats:italic>\n                      -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\n                      <jats:italic>ASXL1<\/jats:italic>\n                      -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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      These findings link immunophenotypic signatures to therapeutic vulnerability, providing a mechanistic explanation for treatment failure in a subset of\n                      <jats:italic>ASXL1<\/jats:italic>\n                      -mutated AML. To address potential small-sample bias, Firth penalized regression was applied. Collectively, this study demonstrates that\n                      <jats:italic>ASXL1<\/jats:italic>\n                      -mutated AML is not a monolithic high-risk entity. The ImmuScore provides a biologically informed and clinically feasible tool to identify truly high-risk\n                      <jats:italic>ASXL1<\/jats:italic>\n                      -mutated patients, potentially guiding personalized therapeutic strategies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1780304","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T04:22:06Z","timestamp":1779164526000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Prognostic heterogeneity in ASXL1-mutated AML and refinement by an immunophenotype-based score"],"prefix":"10.3389","volume":"16","author":[{"given":"Yaming","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Hematology, Key Laboratory of Hematological Malignancies at Affiliated Hospital of Guizhou Medical University","place":["Guiyang, 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