{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T10:58:32Z","timestamp":1791284312210,"version":"4.1.0"},"reference-count":43,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"LSU Health Sciences Center New Orleans School of Medicine"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cancers18193219","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T10:46:29Z","timestamp":1791283589000},"page":"3219","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PODXL2 Expression Is Associated with Inferior Survival, Adverse-Risk Features, and Distinct Transcriptional Programs in Acute Myeloid Leukemia"],"prefix":"10.3390","volume":"18","author":[{"given":"Hyun Min","family":"Ko","sequence":"first","affiliation":[{"name":"School of Medicine, LSU Health Science Center, New Orleans, LA 70112, USA"},{"name":"Department of Microbiology, Genetics and Immunology, LSU LCMC Health Cancer Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Katherine","family":"Scarton","sequence":"additional","affiliation":[{"name":"School of Medicine, LSU Health Science Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Samantha C.","family":"Covey","sequence":"additional","affiliation":[{"name":"School of Medicine, LSU Health Science Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5853-7287","authenticated-orcid":false,"given":"Lucio","family":"Miele","sequence":"additional","affiliation":[{"name":"School of Medicine, LSU Health Science Center, New Orleans, LA 70112, USA"},{"name":"Department of Microbiology, Genetics and Immunology, LSU LCMC Health Cancer Center, New Orleans, LA 70112, USA"},{"name":"Department of Interdisciplinary Oncology, LSU LCMC Health Cancer Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5743-9683","authenticated-orcid":false,"given":"Sun Young","family":"Kim","sequence":"additional","affiliation":[{"name":"School of Medicine, LSU Health Science Center, New Orleans, LA 70112, USA"},{"name":"Department of Microbiology, Genetics and Immunology, LSU LCMC Health Cancer Center, New Orleans, LA 70112, USA"},{"name":"Department of Interdisciplinary Oncology, LSU LCMC Health Cancer Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1159\/000536152","article-title":"Pathophysiology of Acute Myeloid Leukemia","volume":"147","author":"Wachter","year":"2024","journal-title":"Acta Haematol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"308","DOI":"10.3324\/haematol.2022.280801","article-title":"The clinical impact of the molecular landscape of acute myeloid leukemia","volume":"108","author":"Kayser","year":"2023","journal-title":"Haematologica"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1038\/s41588-026-02720-w","article-title":"Epigenetic heterogeneity in AML","volume":"58","author":"Anania","year":"2026","journal-title":"Nat. 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