Genomic and transcriptomic characterization of acute myeloid leukemia with CD123 overexpression

Abstract CD123, the interleukin-3 receptor α chain (encoded by IL3RA), is closely linked to the maintenance of myeloid progenitors. In acute myeloid leukemia (AML), as CD123 is overexpressed on the leukemic stem cells (LSC), several CD123-directed therapeutic strategies are currently undergoing active clinical evaluation. However, a major gap remains in understanding which AML subgroups would benefit most from CD123-targeted interventions in the context of the contemporary International Consensus Classification (ICC). Therefore, in this study, we first confirmed the strong correlation between IL3RA mRNA expressions and CD123 protein levels, and then characterized IL3RA expression patterns across various molecularly defined subgroups based on the 2022 ICC criteria. We observed 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, findings that could be externally validated in independent datasets. Importantly, multivariate Cox regression analysis adjusting for other relevant risk factors demonstrated the independent adverse prognostic effect of IL3RA overexpression in AML. IL3RA-high AML was characterized by upregulated HOX family genes, as well as enhanced LSC transcriptional program and IL-3 pathway activity. Pharmaco-transcriptomic analysis revealed that IL3RA-high AML exhibited selective therapeutic vulnerabilities for venetoclax and INK-128 (sapanisertib). In conclusion, IL3RA overexpression defines a biologically and clinically distinct subgroup of AML. Continued translational research efforts are warranted to refine patient selection and integrate CD123-directed therapeutic modalities into the standard AML treatment protocols.