Thymocyte Selection-Associated High-Mobility Group Box Protein (TOX) Induces Genomic Instability in T-Cell Acute Lymphoblastic Leukemia
Notice bibliographique
Résumé
Abstract MYC and NOTCH are major oncogenic drivers in T-cell Acute Lymphoblastic Leukemia (T-ALL), yet additional collaborating genetic lesions likely collaborate to induce frank malignancy. To identify these factors, a large-scale transgenic screen was completed where 38 amplified and over-expressed genes found in human T-ALL were assessed for accelerating leukemia onset in the zebrafish transgenic model. From this analysis, Thymocyte selection-associated homeobox protein (TOX) synergized with both MYC and NOTCH to induce T-ALL. TOX is dynamically regulated in T cell development with peak expression occurring when thymocytes are actively undergoing T cell receptor (TCR) recombination. TOX is best known for regulating the specification of the mature CD4+ T cells. Despite TOX being genomically amplified in a subset of human and mouse T-ALL and being overexpressed in 100% of human T-ALL, a role for TOX in regulating leukemogenesis has not been reported. Characterization of zebrafish T-ALLs revealed that TOX expands the overall number of malignant T-ALL clones and promoted genomic instability as assessed by changes in DNA content. To identify TOX binding partners, antibody immunoprecipitation studies were performed followed by Tandem Mass Spectrometry. TOX was found to interact with KU70/KU80 but not other DNA repair enzymes including LigaseIV, DNA-PKC, or XRCC4. These results were verified by Western blot analysis and reciprocal immunoprecipitation studies using antibodies specific to KU70/KU80 both in the absence and presence of DNAseI treatment. Given that TOX elevated genomic instability in the zebrafish model and bound specifically to KU70/KU80 – the initiating factors required for Non-Homologous End Joining (NHEJ) repair - we hypothesized that TOX is a negative regulator of double-strand break repair. Fluorescent repair assays were completed in 3T3 fibroblasts and confirmed that TOX inhibits Non-Homologous End Joining (NHEJ). Both the nuclear localization signal and HMG-box were required for the ability of TOX to inhibit double-strand break repair. Dynamic real-time imaging studies confirmed that TOX suppresses recruitment of fluorescent-tagged KU70 to DNA breaks. Importantly, TOX loss of function increased NHEJ in human T-ALL cells and reduced time to DNA repair as assessed by fluorescent Traffic Light Reporter assays and quantitative assessment of 53BP1 and γH2A.X foci resolution following irradiation. Given the prominent role TOX has in T cell development and its coordinated regulation during active TCRβ and TCRα rearrangement, it is likely that the normal function of TOX is to transiently suppress the NHEJ pathway during Recombination-Activating Gene (RAG)-mediated recombination. Prolonging the time to DNA repair would likely facilitate long-range repair across VDJ segments. In the setting of T-ALL, TOX is aberrantly re-activated, thereby suppressing KU70/KU80 function to promote genomic instability and ultimately elevating rates at which acquired mutations and rearrangements are amassed in developing pre-malignant T cells. Disclosures No relevant conflicts of interest to declare.
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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 | 0,000 |
| 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 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 ».