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In acute myeloid leukaemia (AML), as CD123 is overexpressed on the leukaemic stem cells (LSC), several CD123\u2010directed therapies are currently undergoing active clinical evaluation. However, a major gap remains in understanding which AML genetic subgroups would benefit most from interventions targeting CD123 in the context of the contemporary International Consensus Classification (ICC). Therefore, in this study, we first demonstrated the strong correlation between\n                    <jats:italic>IL3RA<\/jats:italic>\n                    mRNA and CD123 protein levels and then characterized\n                    <jats:italic>IL3RA<\/jats:italic>\n                    expression patterns across various molecularly defined subgroups within the ICC framework. We discovered that\n                    <jats:italic>IL3RA<\/jats:italic>\n                    was particularly overexpressed in AML with\n                    <jats:italic>FUS::ERG<\/jats:italic>\n                    ,\n                    <jats:italic>CBFB::MYH11<\/jats:italic>\n                    , high\u2010risk\n                    <jats:italic>KMT2A<\/jats:italic>\n                    fusions,\n                    <jats:italic>NPM1<\/jats:italic>\n                    mutations and\n                    <jats:italic>DEK::NUP214<\/jats:italic>\n                    . Patients with\n                    <jats:italic>IL3RA<\/jats:italic>\n                    overexpression exhibited significantly worse overall and event\u2010free survivals, which could be externally validated. Biologically,\n                    <jats:italic>IL3RA<\/jats:italic>\n                    \u2010high AML was characterized by upregulated\n                    <jats:italic>HOX<\/jats:italic>\n                    family genes as well as LSC and IL\u20103 signalling transcriptional programmes. Pharmaco\u2010transcriptomic analysis revealed that\n                    <jats:italic>IL3RA<\/jats:italic>\n                    \u2010high AML exhibited selective sensitivity to venetoclax and sapanisertib, suggesting potential synergistic opportunities. In conclusion,\n                    <jats:italic>IL3RA<\/jats:italic>\n                    overexpression defines a clinically and biologically distinct subgroup of AML, with unique therapeutic vulnerabilities. Continued research efforts are warranted to integrate CD123\u2010directed therapies into the upfront AML treatment paradigm.\n                  <\/jats:p>","DOI":"10.1111\/bjh.70252","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T08:39:58Z","timestamp":1763455198000},"page":"503-513","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genomic and transcriptomic characterization of acute myeloid leukaemia with\n                    <scp>\n                      <i>IL3RA<\/i>\n                    <\/scp>\n                    overexpression: Prognostic and therapeutic implications revisited"],"prefix":"10.1111","volume":"208","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5052-9445","authenticated-orcid":false,"given":"Chi\u2010Yuan","family":"Yao","sequence":"first","affiliation":[{"name":"Department of Internal Medicine National Taiwan University Hospital  Taipei 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