Abstract B08: Loss of functional Miz-1 impairs c-Myc-dependent B cell lymphomagenesis
Notice bibliographique
Résumé
Abstract Objective: The Myc-interacting zinc finger protein 1 (Miz-1) is a ubiquitous BTB/POZ domain and zinc finger protein that acts as both a transcriptional repressor and activator. The POZ domain of Miz-1 enables protein-protein interactions and facilitates a stable association with chromatin. Miz-1 binds to the proto-oncogen c-Myc and modulates c-Myc target gene expression. Overexpression of c-Myc is an important feature of Burkitt-type B cell lymphomas (BL) caused by c-Myc gene rearrangements. The aim of this project is to determine if Miz-1 is a crucial collaborator of c-Myc in transcriptional regulation of B cells and in the development of c-Myc-dependent B-cell lymphomas. Methods: We are using the Eµ-Myc mouse model to generate Burkitt type c-Myc dependent lymphomas to study the implication of Miz-1 in a c-Myc driven process of malignant transformation. Mice carrying the Eµ-Myc transgene (c-Myc gene placed under the control of Eµ enhancer of the IgH locus) overexpress c-Myc in lymphoid cells and develop a disease similar to Burkitt's lymphoma. Mice that express a conditional non-functional Miz-1 allele lacking the part coding for the POZ domain in B cells (Mb1-Cre-Miz-1fl/fl mice, hereafter called ΔPOZ mice) were crossed with Eµ-Myc transgenic mice. We monitored Eµ-Myc animals expressing wild type or ΔPOZ Miz-1 protein over a period of 500 days. Incidence and latency periods of the development of tumors in both cohorts was compared. Pre-cancerous mice of all genotypes were also investigated to evaluate the influence of Miz-1 during the development of the c-Myc dependant lymphomas. To identify underlying molecular mechanisms, global mRNA expression profiles of pre-neoplastic and tumor cells derived from Eµ-Myc and ΔPOZ/Eµ-Myc mice were performed using high throughput sequencing (RNA-seq). To address the role of Miz-1 in the deregulation of chromatin associated with c-Myc overexpression, chromatin immunoprecipitation coupled to high throughput sequencing (ChIP-seq) was performed on B-lymphoma and pre-tumoral B-cells and compared to normal B-cells. Binding to chromatin of Miz-1 and c-Myc was assessed. Results: ΔPOZ/Eµ-Myc mice develop lymphomas with a significant longer latency and lower incidence than Eµ-Myc mice expressing functional Miz-1 proteins. Additionally, blood analysis of sick animals reveal a lower amount of Large Unstained Cells (LUC) when Miz-1 is mutated. Accordingly, in 40 day old pre-tumoral ΔPOZ/Eµ-Myc animals compared to Eµ-Myc mice, less pre-B and/or pro-B cells were observed in lymphoid organs and little or no LUC were present in the blood. This suggests that Myc driven lymphoma and leukemia is impaired when a ΔPOZ Miz-1 protein is expressed. Our RNA-seq analyses of pre-neoplastic and tumor cells revealed that the expression of ΔPOZ Miz-1 induces deregulation of several genes belonging to different GO (Gene Ontology) functions like “small GTPase-mediated signal transduction”. Interestingly, comparision of RNA-seq and Miz-1 ChIP-seq analyses indicates that some Miz-1 bound genes are deregulated in cells from ΔPOZ/Eµ-Myc mice (e.g: Aurora kinase A (Aurka)). Conclusion: Our data indicate that Miz-1 is required for the efficient development of aggressive c-Myc-driven lymphomas. Miz-1 is probably cooperating with c-Myc in the abnormal transcriptional program that is occuring in lymphoma cells. Therefore, targeting Miz-1 in B-lymphomas could lead to the development of new therapeutic approaches. Citation Format: Julie Ross, René Winkler, Charles Vadnais, Marissa Rashkovan, Christian Kosan, Tarik Möröy. Loss of functional Miz-1 impairs c-Myc-dependent B cell lymphomagenesis. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B08.
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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) | 0,000 | 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 ».