P422: TARGETING THE WT1MUT-MIR-193A TRANSCRIPTIONAL AXIS WITH INT-1B3, A NOVEL LIPID NANOPARTICLE-FORMULATED MIR-193A-3P MIMIC IN ACUTE MYELOID LEUKEMIA
Notice bibliographique
Résumé
Background: Wilms Tumor 1 mutations (WT1mut) is a negative prognostic factor in acute myeloid leukemia patients with normal karyotype (CN-AML) with no tailored treatment. Considering that AML patients with WT1mut are characterized by a DNA hypermethylation signature, we hypothesized that epigenetic silencing of downstream genes supports the growth of WT1mut AML cells and could represent therapeutic drug targets. Aims: Here, we explore the tumor suppressor potential of miR-193a in CN-AML. We aim to uncover its full target range, both 5p and 3p arms, with a goal of utilizing it as an effective therapeutic for AML cells through a lipid nanoparticle formulation. Methods: We took advantage of a primary murine AML transplantation model based on the combined overexpression of Hoxa9 and Meis1 (H9M), which are frequently upregulated in CN-AML, human AML cell lines and primary AML samples. Results: Analysis of publicly available methylation and miRNA expression data suggested transcriptional repression by increased DNA methylation at the miR-193a locus in WT1mut AML cells. MiR-193a is located within a large CpG island and has been previously implicated as a tumor suppressor in AML patients, however, its regulation and impact in CN-AML is unknown. MiRNA-Seq data of 300 CN-AML patients subsequently confirmed repression of miR-193a transcript levels in patients with WT1mut. Moreover, lentiviral overexpression of WT1mut in human AML cell lines conferred low miR-193a levels, whereas overexpression of WT1wt increased miR-193a even in the presence of endogenous WT1mut, highlighting the role of WT1wt as a transcriptional activator of miR-193a in AML cells. Enforced expression of miR-193a significantly delayed AML onset in vivo. In addition, overexpression of miR-193a in multiple human AML cell lines and primary patient samples impaired AML cell growth and colony-forming capacity while promoting monocytic differentiation, underscoring its role as potent tumor suppressor. To define the target range of each arm, we performed RNA-Seq in human AML cells transfected with miR-193a-3p or 5p mimics. Subsequent gene set enrichment analysis suggested that miR-193a, in particular miR-193a-3p modulates the MAPK pathway and exogenous interactions between AML cells and the immune system. Therapeutic modulation of miRNA levels in cancer patients has been an attractive concept due to their ability to impact on multiple pathways, but technical limitations in their delivery and tissue enrichment have prevented translation from the preclinical stage to patients. To overcome this, we tested a novel lipid-nanoparticle (LNP) formulation of miR-193a-3p (INT-1B3), which is currently being investigated in a phase I clinical trial for solid tumor patients (NCT04675996). To evaluate the effect of INT-1B3 on leukemogenesis in vivo, we engrafted H9M cells in a murine host with an intact immune system, allowing INT-1B3 to exert its immunomodulatory effects. Biweekly i.v. treatments of INT-1B3 after H9M cell transplantation prevented AML formation, highlighting the potent anti-leukemic activity of this miRNA based therapeutic. Summary/Conclusion: We uncover a previously unknown regulatory mechanism between WT1mut and miR-193a in AML cells, which provides a novel therapeutic target for a miR-193a based therapeutic for AML patients. Keywords: WT1, Immunomodulation, Acute myeloid leukemia, Nanoparticle
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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,003 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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; les deux têtes enseignantes s’accordent sur ce qui est montré ici.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».