Abstract 5411: The IL-23 receptor localizes intracellularly in AML and stem cells where it regulates mitotic spindle formation to maintain cell viability
Notice bibliographique
Résumé
Abstract IL-23 receptor (IL-23R) is canonically a T cell surface cytokine receptor known for its role in inflammatory diseases. In this study, we demonstrated that IL-23R localizes intracellularly in AML where it regulates mitotic spindle formation. Differential gene expressions were analyzed in AML samples compared to normal controls. Of the upregulated processes, the mitotic spindle ontology was most enriched. Analyzing all protein coding genes for their correlation to the mitotic spindle ontology surprisingly returned IL-23R as a top hit. We confirmed IL-23R expression in 7 of 7 tested AML cell lines and 15 of 20 primary AML patient samples. Protein expression was >2 fold higher in AML compared to normal hematopoietic (n=5) and CD34+ sorted cells (n=3).Canonical IL-23R cell surface expression was confirmed in T cells, but minimal amounts were detected on AML cells. Rather, in AML cells, primary AML samples, and AML stem cells, IL-23R was detected intracellularly as determined by 4 different modalities using 4 different epitope targeting antibodies. IL-23R’s heterodimeric subunit, IL-12Rβ1, was also detected intracellularly in AML cells. We performed BioID mass spectrometry to identify novel interactors with IL-23R. Pathway analysis of interactors returned mitotic spindle formation as a top pathway. We confirmed interactions between IL-23R and mitotic spindle proteins (NuMA, TMEM201, TACC1, BAG6) via proximity ligation assays in bulk and leukemic stem cell (LSC) sorted AML cells. Furthermore, in bulk AML and LSC sorted fractions, we demonstrated that IL-23R colocalized with the mitotic spindle and centrosomes via confocal microscopy. IL-23R interacted with the mitotic spindle via its (S/T)x(I/L)P motif (amino acids 588-591). IL-12Rβ1 was also found at the mitotic spindle with exogenous IL-23 in culture promoting intracellular translocation of IL-23R. Depletion of IL-23R led to dysregulation of the mitotic spindle with spindle defects such as multipolarity and lagging chromosomes. Additionally, in IL-23R depleted mitotic AML cells, NuMA has decreased localization to mitotic spindle poles thus attenuating its ability to regulate mitotic spindle assembly. Knockdown of IL-23R reduced proliferation and clonogenic growth, reduced marrow engraftment, and increased differentiation of AML cells, thus demonstrating an effect on the leukemia initiating cells. In normal hematopoietic cells, however, knockdown of IL-23R did not impair engraftment. Consistent with this, constitutive homozygote IL-23R knockout mice had no difference in complete blood counts and stem cell number/function compared to wild type mice. In summary, intracellular IL-23R regulates mitotic spindle formation to maintain AML and stem cell growth and viability. We demonstrated a novel function and intracellular localization for IL-23R and its potential as a therapeutic target in AML. Citation Format: Nathan Duong, Dilshad H. Khan, Geethu E. Thomas, Yue Feng, Rose Hurren, Jong Bok Lee, Jonathan St-Germain, Lily Drimmer, Yongran Yan, Lan Xin Zhang, Dakai Ling, Mary L. Ma, Neil MacLean, Marcela Gronda, Vincent Rondeau, Brandon D. Brown, Laura Matellán, Courtney L. Jones, Hong Chang, Andrea Arruda, Stephanie Xie, Laurence Pelletier, Mark D. Minden, Li Zhang, Steven M. Kornblau, Brian Raught, Kevin Jacobs, Max G. Jacobs, Daniel Goede, Vito Spadavecchio, Aaron D. Schimmer. The IL-23 receptor localizes intracellularly in AML and stem cells where it regulates mitotic spindle formation to maintain cell viability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5411.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».