Genomic and transcriptomic characterization of acute myeloid leukaemia with IL3RA overexpression: Prognostic and therapeutic implications revisited

CD123 (encoded by IL3RA) is intricately linked to the maintenance of haematopoietic progenitors. In acute myeloid leukaemia (AML), as CD123 is overexpressed on the leukaemic stem cells (LSC), several CD123-directed 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 IL3RA mRNA and CD123 protein levels and then characterized IL3RA expression patterns across various molecularly defined subgroups within the ICC framework. We discovered that IL3RA was particularly overexpressed in AML with FUS::ERG, CBFB::MYH11, high-risk KMT2A fusions, NPM1 mutations and DEK::NUP214. Patients with IL3RA overexpression exhibited significantly worse overall and event-free survivals, which could be externally validated. Biologically, IL3RA-high AML was characterized by upregulated HOX family genes as well as LSC and IL-3 signalling transcriptional programmes. Pharmaco-transcriptomic analysis revealed that IL3RA-high AML exhibited selective sensitivity to venetoclax and sapanisertib, suggesting potential synergistic opportunities. In conclusion, IL3RA overexpression defines a clinically and biologically distinct subgroup of AML, with unique therapeutic vulnerabilities. Continued research efforts are warranted to integrate CD123-directed therapies into the upfront AML treatment paradigm.