PODXL2 Expression Is Associated with Inferior Survival, Adverse-Risk Features, and Distinct Transcriptional Programs in Acute Myeloid Leukemia
- 1School of Medicine, LSU Health Science Center, New Orleans, LA 70112, USA
- 2Department of Microbiology, Genetics and Immunology, LSU LCMC Health Cancer Center, New Orleans, LA 70112, USA
- 3Department of Interdisciplinary Oncology, LSU LCMC Health Cancer Center, New Orleans, LA 70112, USA
Abstract
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.
Related
- Baseline Tumor Transcriptional Features and Event-Free Survival After Anti-CD19 CAR T-Cell Therapy with Axicabtagene Ciloleucel in Large B-Cell Lymphoma: An Exploratory Reanalysis of the Randomized ZUMA-7 Trial
- Association of VCP/p97 Expression with Clinicopathological Features and Overall Survival in Endometrioid Endometrial Carcinoma
- Osteopenia Is Associated with Inferior Survival After Deceased-Donor Liver Transplantation
- A transcriptional signal associated with mesenchymal stromal cells predicts overall survival in B cell acute lymphoblastic leukemia
- FLT3 expression and immune-associated transcriptional signatures in prostate cancer
BibTeX
@article{ko2026podxl2,
title = {{PODXL2 Expression Is Associated with Inferior Survival, Adverse-Risk Features, and Distinct Transcriptional Programs in Acute Myeloid Leukemia}},
author = {Hyun Min Ko and Katherine Scarton and Samantha C. Covey and Lucio Miele and Sun Young Kim},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18193219},
url = {https://europepmc.org/article/PMC/PMC13664358},
note = {CC BY},
}
RIS
TY - JOUR
TI - PODXL2 Expression Is Associated with Inferior Survival, Adverse-Risk Features, and Distinct Transcriptional Programs in Acute Myeloid Leukemia
AU - Hyun Min Ko
AU - Katherine Scarton
AU - Samantha C. Covey
AU - Lucio Miele
AU - Sun Young Kim
PY - 2026
DA - 2026/10/01
JO - Cancers
DO - 10.3390/cancers18193219
UR - https://europepmc.org/article/PMC/PMC13664358
AB - 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.
SN - 2072-6694
ER -