Role of DOT1L in epigenetic regulation of the HOXA9 gene expression in mixed lineage leukemia
Notice bibliographique
Résumé
Mixed lineage leukemia (MLL) is often characterized by chromosomal translocations involving the lysine methyltransferase 2A (KMT2A) gene with various partner genes, creating fusion proteins that can mistarget DOT1L to the homeobox A9 (HOXA9) gene, leading to HOXA9 expression. Among the possible translocations with KMT2A, the fusion of KMT2A with myeloid/lymphoid or mixed-lineage leukemia; translocated to 3 (MLLT3), also known as KMT2A-MLLT3, is particularly significant because it has been reported in more than 50% of pediatric and 25% of adult acute myeloid leukemia cases. The KMT2A-MLLT3 translocation creates the fusion protein that aberrantly recruits DOT1L (disruptor of telomeric silencing 1-like) and other chromatin-modifying enzymes to the HOXA9 locus, resulting in increased HOXA9 gene expression. HOXA9 expression disrupts normal hematopoietic differentiation and contributes to the development of mixed lineage leukemia by promoting the proliferation and survival of leukemic cells. My research focuses on unraveling the mechanisms that drive heightened DOT1L activity and its specific targeting to HOXA9, pivotal for the robust transcription observed in MLL. Our results showed that the HOXA cluster is marked by several active marks and chromatin modifying enzymes including H3K27ac, H3K4me3, H3K36me3, H3K79me2, DOT1L and DNase I. The heavy decoration by these active marks and proteins indicates that HOXA9 has an unstable chromatin structure, which reflects higher nucleosome turnover over the HOXA9 region. Higher turnover makes the chromatin more accessible to the transcriptional machinery, thereby increasing HOXA9 expression. Histone H3 has three forms: H3.1 and H3.2 as canonical, and H3.3 as a variant. The H3.3 variant can be more incorporated into nucleosomes with higher turnover, which can further enhance the transcription of the HOXA9 gene in MOLM 13 cells. Our results showed that the H3K79me2 level, which indicates DOT1L enzyme activity, is higher in MOLM-13 cells with the KMT2A-MLLT3 translocation. Several studies have shown that DOT1L activity depends on Histone H2B monoubiquitination at Lys 120 (H2BK120ub), a key modification in transcription elongation. Our results also revealed that the level of H2BK120ub is higher in MOLM-13 cells, which have increased DOT1L activity, suggesting a direct relationship between H2BK120ub and DOT1L activity in these cells. Bortezomib, an FDA-approved drug commonly used in clinical practice for multiple myeloma, was employed to investigate its effect on epigenetic marks involved in transcription elongation including the H3K79me2, H3K36me3, and H2BK120ub in MOLM-13 cells. Treatment with 5 nM bortezomib demonstrated significant reductions in H2BK120ub levels, H3K79me2, and HOXA9 gene expression in MLL. My findings underscore the critical role of H2BK120ub in regulating DOT1L methyltransferase activity and HOXA9 expression in MOLM-13 cells. These compelling results position bortezomib as a promising therapeutic avenue for treating MLL, offering new hope for patients affected by this challenging disease.
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 | 0,000 |
| 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 ».