PODXL2 Expression Is Associated with Inferior Survival, Adverse-Risk Features, and Distinct Transcriptional Programs in Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) is characterized by substantial biological heterogeneity that is incompletely captured by current risk-classification frameworks. Podocalyxin-like 2 (PODXL2), a CD34-family transmembrane sialomucin implicated in tumor progression in solid tumors, remains poorly characterized in AML. Methods: We conducted integrated clinical, genomic, transcriptomic, regulatory network, and ex vivo drug-response analyses using two independent AML cohorts, TCGA-LAML and BeatAML. Results: Elevated PODXL2 expression was consistently associated with inferior overall survival across both cohorts, including after adjustment for established clinical risk factors. PODXL2-high AML was enriched for adverse-risk features, including ELN 2022 adverse-risk classification, poor-risk cytogenetics, and TP53 mutations, whereas IDH2 mutations were more frequent in PODXL2-low AML. Transcriptomic analyses identified a distinct PODXL2-high state characterized by enrichment of MYC and E2F target programs, cell-cycle progression, DNA repair, oxidative phosphorylation, mTORC1 signaling, and metabolic pathways. Regulatory network analyses demonstrated enhanced MYC/E2F-associated regulatory activity. PODXL2-high AML also exhibited altered differentiation-state features, characterized by reduced representation of monocyte-like and conventional dendritic cell-like malignant cell states. Ex vivo drug-response profiling identified distinct PODXL2-associated response patterns, including reduced sensitivity to OTX-015 and SRC-family kinase inhibitors. Conclusions: PODXL2 expression is associated with adverse clinical and molecular features, distinct transcriptional programs, altered differentiation states, and differential ex vivo drug-response patterns in AML. These findings identify PODXL2 expression as a marker associated with adverse clinical and molecular features and inferior survival in AML, although its prognostic discrimination as a standalone marker is modest. Further functional and prospective studies are warranted to establish its biological and clinical significance.