Abstract C225: IL1RAP as functionally relevant target for stem-cell directed therapy in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
Notice bibliographique
Résumé
Abstract Despite the established use of poly-chemotherapy, relapse continues to be the most common cause of death in AML and MDS and cure rates remain below 20%. AML/MDS arise following the accumulation of stepwise genetic and epigenetic changes in hematopoietic stem and progenitor cells (HSPC). Utilizing a novel strategy of parallel transcriptional analysis of sorted HSPC populations in distinct subtypes of AML, we compared the gene expression in AML HSPC with identical compartments from age-matched healthy controls and identified Interleukin 1 receptor accessory protein (IL1RAP) as one of the most significantly upregulated genes in HSPC in all examined subtypes of AML. Fluorescence in situ hybridization of sorted IL1RAP+ and IL1RAP- cells from patients with monosomy 7 AML (-7) indicated that the aberrant clone was restricted to IL1RAP+ cells, demonstrating that IL1RAP overexpression is a distinguishing feature of the -7 clone. Multivariate analysis of a large cohort of patients with normal karyotype AML showed that patients with high IL1RAP levels had inferior overall survival than patients with lower IL1RAP levels, suggesting an independent prognostic value for this molecule in AML. IL1RAP expression levels in MDS were found elevated on stem cells of patients with high risk disease, proposing a role of IL1RAP in higher risk MDS and progression to AML. Downregulation of IL1RAP expression by lentivirally expressed shRNAs decreased clonogenicity in cell lines and AML/MDS primary patient samples, induced apoptosis of AML cells, and reduced proliferation of AML cells and infiltration of hematopoietic organs in vivo. IL1RAP is a transmembrane protein required for signaling through several receptors of the IL1 family. Downregulation of IL1RAP expression in AML cells led to phosphorylation changes in several kinases and their substrates suggesting participation of IL1RAP in multiple signaling pathways and highlighting its potential as therapeutic target. We investigated whether inhibition of IL1RAP with pharmacological compounds is feasible and effective. Antibody-mediated inhibition of IL1RAP led to inhibition of AML cell growth in vitro. In addition, we designed peptides to interfere with IL1RAP-receptor interactions which lead to inhibition of AML cell growth. Both types of agents are being further tested and optimized. In summary, our study reveals IL1RAP as aberrantly expressed on HSPC of AML and high-risk MDS patients. Inhibition of IL1RAP is feasible and functionally effective, and thus has the potential to lead to novel therapies specifically directed at such stem cells. Beyond IL1RAP, our study provides a map of dysregulated transcripts in HSPC from patients with AML, which may offer further opportunities for therapeutic intervention. The strategy of comparative analysis of sorted stem and progenitor cells in cancer versus healthy controls may be applicable to other type of cancers with a suspected stem cell origin, and instrumental for the identification of targets for stem cell-directed therapy. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C225. Citation Format: Laura Barreyro, Kelly Mitchell, Britta Will, Boris Bartholdy, Li Zhou, Tihomira Todorova, Robert Stanley, Susana Ben-Neriah, Cristina Montagna, Samir Parekh, Andrea Pellagatti, Jacqueline Boultwood, Elisabeth Paietta, Rhett Ketterling, Larry Cripe, Hugo Fernandez, Peter Greenberg, Jacob Rowe, Martin Tallman, Christian Steidl, Constantine Mitsiades, Amit Verma, Ulrich Steidl. IL1RAP as functionally relevant target for stem-cell directed therapy in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C225.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
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 tête enseignante, 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 ».