Abstract 2991: Cytoplasmic mislocalization of CTCF by NPM1c in acute myeloid leukemia resulting in inhibited CTCF regulatory functions generating aberrant genetic and epigenetic profiles
Notice bibliographique
Résumé
Abstract AML is not a single disease but rather a collection of diseases caused by a variety of mutations. About 30% of AML cases are characterized by a TCTG insertion in the exon 12 of Nucleophosmin 1 (NPM1). Due to this mutation, mutant NPM1 (NPM1c) is mislocalized and maintained predominantly in the cytoplasm of the cell. Previously it had been reported that NPM1 binds to CCCTC binding factor (CTCF). Based on this observation we hypothesized that NPM1c would mislocalize CTCF into the cytoplasm, preventing CTCF's access to binding sites in the nucleus, and allowing for epigenetic misregulation of gene expression. To demonstrate that NPM1c could mislocalize CTCF to the cytoplasm we used confocal microscopy. While CTCF was completely nuclear in cells expressing NPM1, CTCF was present in the nucleus and the cytoplasm of cells expressing NPM1c. The cytoplasmic interaction of NPM1c and CTCF was confirmed by immunoprecipitation and western blotting. Using fluorescently tagged sub-fragments of NPM1c and CTCF we found that a.a. 1-264 of CTCF interacted with a.a. 244-298 of NPM1c. CTCF has multiple effects on gene expression related to the level of CTCF in the cell/nucleus; overexpression of CTCF leads to cell senescence while reduced expression can lead to immortalization. Such effects are likely mediated by the effects of CTCF on gene expression and alternate splicing. Increased expression of HOXA9 is a characteristic of NPM1c AML and has been shown to be affected by CTCF binding between HOXA9 and HOXA7 in IMR90 cells. To determine if NPM1c would affect HOXA9 expression in IMR90 cells, we infected the cells with NPM1c or NPM1. Similar to CTCF knockdown in IMR90 cells, there was increased expression of HOXA9 in the NPM1c, but not NPM1 modified cells. Moreover, the IMR90 cells expressing NPM1c became immortal. Using chromatin immunoprecipitation we found that there was reduced binding of CTCF to the CTCF binding site 2kb downstream of HOXA9 in the IMR90 cells expressing NPM1c. Reduced CTCF binding to this site was observed in the NPM1c mutant human cell line OCI-AML-3 but not NB4 cells, an AML cell line, that lacks the mutation. Loss of CTCF binding in NPM1c expressing cells was further demonstrated by changes in CTCF mediated alternate splicing and enhancer blocking activity using reporter assays. Finally, interrogation of the TCGA AML data set showed increased methylation of CTCF binding sites in NPM1c AML. This is in keeping with de novo methylation that occurs when CTCF no longer binds to its cognate site. Based on these studies we propose that the transforming effect of NPM1c is due, in large part, to its ability to mislocalize CTCF and suggests that targeting the interaction between these two proteins could be of potential therapeutic benefit. Citation Format: Atom Wang, Youqi Han, Peikun Chen, Nanyang Jia, Mark D. Minden. Cytoplasmic mislocalization of CTCF by NPM1c in acute myeloid leukemia resulting in inhibited CTCF regulatory functions generating aberrant genetic and epigenetic profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2991.
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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».