Abstract 1646: IL-23R is a regulator of the mitotic spindle and is critical for cell viability in AML
Notice bibliographique
Résumé
Abstract To identify novel biological vulnerabilities in AML, we searched for gene ontologies that were upregulated in AML compared to normal hematopoietic cells. Of the upregulated processes, the mitotic spindle ontology was a top hit. Unexpectedly, expression of the IL-23 receptor (IL-23R) showed a strong positive correlation with the mitotic spindle ontology. IL-23R is a cell surface cytokine receptor that is canonically expressed on T cells, but not known to have a role in AML. In 7 of 7 tested AML cell lines and 15 of 20 primary AML patient samples, IL-23R protein was expressed >2 fold higher compared to mean IL-23R in normal mononuclear hematopoietic cells (n=5) and CD34+ cells (n=3). IL-23R is classically a T cell surface receptor and we confirmed localization to the cell surface in T cells. However, only small amounts of IL-23R were present on the cell surface of AML cell lines and primary AML samples. Rather, in AML cells, primary AML samples, and AML stem cells, IL-23R was located intracellularly as determined by 4 different modalities and 4 different antibodies directed against 4 different epitopes of the receptor. Of note, only the full-length IL-23R protein was detected by immunoblotting. We also detected IL-23R’s heterodimeric partner, IL12Rβ1, in AML cells. To understand the function of intracellular IL-23R, we used BioID mass spectrometry to identify proteins that interacted with IL-23R. Pathway analysis of interacting proteins identified mitotic spindle formation as the top pathway. Using Proximity Ligation Assays, we validated interactions with mitotic spindle proteins, and BioID hits, NUMA, TMEM201, TACC1, and BAG6 in AML cells. By confocal microscopy, we demonstrated that IL-23R colocalized with the mitotic spindle and centrosomes in AML cells and primary AML samples. 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 in complex with IL-23R at the mitotic spindle in AML cells. Additionally, it was discovered that the cytokine, IL-23, promoted translocation of IL-23R to the mitotic spindle through clathrin-mediated endocytosis. Knockdown and knockout of IL-23R in AML cells led to dysregulation of the mitotic spindle with multipolarity, lagging chromosomes, and other spindle defects. Knockdown of IL-23R also reduced proliferation, clonogenic growth, and marrow engraftment of AML cells and primary AML samples. In contrast, knockdown of IL-23R in normal CD34+ cells did not impair engraftment. Likewise, constitutive homozygote IL-23R knockout mice had no difference in complete blood counts and stem cell number/function compared to wild type. In summary, IL-23R interacts with the mitotic spindle and centrosome where it regulates mitotic spindle formation and is critical for AML cell viability. Thus, we discover a novel function for IL-23R and a potential therapeutic target for this disease. Citation Format: Nathan Duong, Dilshad H. Khan, Geethu E. Thomas, Rose Hurren, Jong Bok Lee, Jonathan St-Germain, Lily Drimmer, Yongran Yan, Neil Maclean, Marcela Gronda, Vincent Rondeau, Brandon D. Brown, Courtney L. Jones, Hong Chang, Andrea Arruda, Mark D. Minden, Li Zhang, Steven M. Kornblau, Brian Raught, Vito Spadavecchio, Aaron D. Schimmer. IL-23R is a regulator of the mitotic spindle and is critical for cell viability in AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1646.
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 | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 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) | 0,004 | 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 ».