{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T12:09:05Z","timestamp":1792238945607,"version":"4.4.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T00:00:00Z","timestamp":1746057600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Acute lymphoblastic leukemia (ALL) is a hematological malignancy with high survival rates in children; however, certain high-risk subtypes pose significant challenges due to poor prognosis and frequent relapse. Ubiquitination, a post-translational modification critical for protein regulation, has been implicated in various cancer processes, yet its role in ALL remains poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using the TARGET database, we identified molecular subtypes of ALL through consensus clustering based on ubiquitination-related genes (URGs). A nine-gene prognostic model was constructed using LASSO and Cox regression analyses. The immunological landscape variations between high- and low-risk groups were assessed using immune cell infiltration analysis and functional enrichment studies. <jats:italic>FBXO8<\/jats:italic> was further explored through functional experiments <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Four ALL subtypes with distinct survival outcomes were identified, with Cluster D representing the high-risk group. Patients were divided into high- and low-risk groups using the nine-gene predictive model, and <jats:italic>FBXO8<\/jats:italic> was found to be a significant protective factor. According to immune landscape analysis, high-risk groups had an immunosuppressive microenvironment that was correlated with <jats:italic>FBXO8<\/jats:italic> expression and marked by an increase in regulatory T cells and M2 macrophage infiltration. <jats:italic>In vitro<\/jats:italic> functional assays, <jats:italic>FBXO8<\/jats:italic> knockdown notably enhanced cell proliferation and suppressed apoptosis in ALL cells. In <jats:italic>FBXO8<\/jats:italic>-knockdown mouse models, <jats:italic>in vivo<\/jats:italic> investigations demonstrated increased tumor growth, reduced apoptosis, and diminished survival rates.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This work identifies <jats:italic>FBXO8<\/jats:italic> as a crucial therapeutic target and prognostic biomarker for ALL. Knockdown of <jats:italic>FBXO8<\/jats:italic> led to the suppression of apoptosis and increased tumor growth, suggesting potential therapeutic applications. These results highlight the need for more investigation into ubiquitination-related pathways and offer important new insights into high-risk ALL.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1554231","type":"journal-article","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T05:38:39Z","timestamp":1746077919000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Ubiquitination and ALL: Identifying FBXO8 as a prognostic biomarker and therapeutic 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