Molecular Dissection of Nup98-HoxA9 Oncogenic Activity Using Drosophila
Notice bibliographique
Résumé
Abstract Roughly three-quarter of the genes associated with human diseases have fly counterparts. This high degree of conservation, combined to a wide range of genetic tools, makes Drosophila an attractive model to study basic mechanisms lying at the heart of various human disorders. Several oncogenes mediate their effects by interfering with specific cell machinery components common to all eukaryotes. The systematic identification of cell components influencing the activity of oncogenes should therefore accelerate the characterization of those oncogenes. Toward this goal, we take advantage of Drosophila molecular genetics to identify conserved genes that functionally interact with oncogenes. Our effort currently focuses on the t(7;11)(p15;p15) translocation associated with acute myeloid leukemia (AML) and which fuses the N-terminal part of Nucleoporin 98 (NUP98) to the C-terminal part of the transcription factor HOXA9. As homologues of NUP98 and HOXA9 are present in flies, we hypothesized that expression of NUP98-HOXA9 during development will affect some of the same protein networks that are perturbed in human hematopoietic cells. We successfully conducted several modifier screens in the past by exploiting dosage-sensitive phenotypes specifically induced in the eyes. To that end, we expressed NUP98-HOXA9 during eye development, which interestingly phenocopied Homothorax (HTH) overexpression in its ability to block eye development and promoted head cuticle formation. HTH is the homologue of MEIS1; a DNA-binding co-factor for HOXA9 that functions with a third partner, PBX, and which together form a ternary complex that regulates gene expression. Importantly, we found that the NUP98-HOXA9 eye phenotype was suppressed by mutations in the hth and exd (Drosophila pbx) genes, thus lending support to the specificity of the phenotype. In agreement with this, a structure/function analysis of NUP98-HOXA9 conducted in the fly eye narrowed down the same functional domains/motifs as those that had been identified using mouse models, namely, the HOXA9 homeodomain, the HOXA9 ANW motif (a PBX-interaction site) and the NUP98 portion. Remarkably, we also found that NUP98-HOXA9 and HTH/MEIS synergistically induced cell proliferation when coexpressed in the developing eye. As a result, large tissue overgrowths were produced. The cooperation observed in this experimental setting is reminiscent of the ability of MEIS1 to accelerate AML onset when co-expressed with NUP98-HOXA9 in mouse models. Moreover, we found that the collaboration strictly depends on endogenous EXD/PBX as its depletion by RNAi completely prevents overgrowth formation. Together, these findings provide compelling evidence that the NUP98-HOXA9 fly model recapitulates several of the key functional features that had been established in mammals for this oncogene and thus should prove useful to further delineate the immediate events disturbed by NUP98-HOXA9 expression. Based on these premises, we conducted a genetic screen to isolate dominant modifiers of the NUP98-HOXA9 eye phenotype. Approximately 100,000 fly progeny have been screened, which led to the isolation of a few hundred mutations acting either as suppressors or enhancers. Several complementation groups have now been uncovered and their molecular identification is currently underway. Validation of relevant genes in mouse leukemia models will be conducted to confirm their significance with respect to HOX-dependent leukemia. The NUP98-HOXA9 fly model as well as the early findings of the screen will be presented.
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) | 0,000 | 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) | 0,000 | 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 ».