Abstract A019 Genetic and epigenetic characterization of <i>NUP98</i>-rearranged leukemia
Notice bibliographique
Résumé
Abstract Introduction Pediatric acute myeloid leukemia (AML) with NUP98 rearrangements (NUP98r) is associated with dismal prognoses. NUP98 fusion partners are linked with specific AML subtypes, such as NUP98::NSD1 with myeloblastic AML and NUP98::KDM5A with acute megakaryocytic leukemia (AMKL). Although mostly present in AML, various NUP98r are also found in other malignancies such as T-cell acute lymphoblastic leukemia (T-ALL) and myelodysplastic syndrome (MDS). Despite genomic studies showing associations between FLT3 internal tandem duplications (FLT3-ITD) and WT1 mutations with NUP98::NSD1 AML, the genome-wide mutational status of NUP98r leukemias is to be elucidated. Also, experimental models showed that NUP98 fusion oncoproteins (FOs) regulate gene expression by binding to genomic loci such as HOX genes or MEIS1; however, how different partners contribute to specific diseases remains unstudied. Methods We established a pediatric NUP98r leukemia cohort consisting of 185 samples from 177 cases from our institute, public databases, or collaborators. AML is the dominant disease (n=154), whereas it also included T-ALL (n=18), therapy-related myeloid neoplasms (t-MN, n=4), and MDS (n=1). RNA-sequencing (RNA-seq) data was obtained for all samples, and whole-genome/exome sequencing (WGS/WES) data was obtained from 94 samples. Fusion genes were called from RNA-seq. Somatic alterations were called from both WGS/WES and RNA-seq. The epigenetic status and NUP98 FO-binding of 14 cases were studied using CUT&RUN with antibodies against the N-terminal NUP98, H3K27ac, H3K4me, and K3H27ac. Results Among 177 cases, NUP98::NSD1 was most prevalent (n=92) followed by NUP98::KDM5A (n=45). This cohort also included 11 cases with NUP98::RAP1GDS1 enriched in T-ALL and immature AML, rarely reported in previous NUP98r studies. Genomic profiling confirmed known associations with NUP98::NSD1 AML with FLT3-ITD or WT1, along with novel associations represented by NOTCH1, CCND3, and NRAS mutations with NUP98r T-ALL. Transcriptional analyses with other AML subtypes (n=821) showed NUP98r cases are distributed in five large clusters, where fusions and mutations were associated with specific clusters but not exclusively, suggesting that fusion partners, cooperating alterations, and differentiation states contribute to the disease phenotypes. Epigenetic profiling of 14 cases (NSD1: n=5, KDM5A: n=6, RAP1GDS1: n=3) showed that H3K27ac patterns reflect disease types while H3K27me3 and NUP98-FO binding patterns are intrinsic to fusion partners. NUP98 FOs bound to genes commonly expressed in NUP98r leukemia such as HOXA-B genes or ETV6, whereas NUP98-FOs bound to differentiation-related genes depending on the leukemia subtype (e.g., NUP98::KDM5A binding to the GFI1B loci in AMKL). Conclusion These data suggest that NUP98 FOs specify disease types by directly regulating differentiation-related genes. Further investigation by introducing somatic mutations (e.g., WT1 mutations, RB1 loss) in NUP98r models would reveal its contribution to gene regulation and disease types. Citation Format: Masayuki Umeda, Nicole Michmerhuizen, Ryan Hiltenbrand, Juan M. Barajas, Michael P. Walsh, Guangchun Song, Jing Ma, Tamara Westover, Cristina Mecucci, Danika Di Giacomo, Franco Locatelli, Riccardo Masetti, Salvatore Bertuccio, Martina Pigazzi, Ilaria Iacobucci, Charles G. Mullighan, Jeffery M. Klco. Genetic and epigenetic characterization of NUP98-rearranged leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A019.
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 | 0,001 | 0,001 |
| 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) | 0,003 | 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 ».