Cryptic NUP98/NSD1 Translocations Are Highly Prevalent in FLT3/ITD-Positive Acute Myeloid Leukemia and Lead to High Rate of Induction Failure. Report From Children's Oncology Group
Notice bibliographique
Résumé
Abstract Abstract 529 The nucleoporins (NUP) are a family of proteins, which form the building blocks of the nuclear pore complex. Translocations involving NUP family members NUP214 and NUP98 have been reported in acute myeloid leukemia (AML). DEK/NUP214 (also known as DEK/CAN, t(6;9)) is a known translocation in AML that is highly associated with FLT3/ITD and adverse outcome (see presentation by Moraleda P. et al). By Whole Transcript Sequencing (RNA Seq) we identified 2 cases of NUP98/NSD1 fusions by patients with cytogenetically normal (CN-) AML, both with FLT3/ITD. Recent studies by Hollink I. et al demonstrated high prevalence of FLT3/ITD in patients with NUP98/NSD1 translocations and its association with adverse outcome. Given the significant overlap between DEK/NUP214, NUP98/NSD1 fusions and FLT3/ITD, we studied the prevalence of these fusion transcripts in patients with FLT3/ITD to define the prognostic significance of genomic alteration and their contribution to clinical outcome. Pretreatment samples from patients with FLT3/ITD (N=117) as well as those with CN-AML (N=166) treated on COG-AAML0531 underwent evaluation for NUP98/NSD1 fusion transcripts RT-PCR. Fusion transcripts, as well as the break point junction was verified by Sanger sequencing. Presence of NUP98/NSD1 transcript was correlated with disease characteristics and clinical outcome in patients with FLT3/ITD. In patients with FLT3/ITD (N=117) NUP98-NSD1 was detected in 15 patients (13%). Demographics and disease characteristics of FLT3/ITD patients were compared between those with and without NUP98/NSD1. There were no significant differences in the median age (11 vs. 13 years, p=0.19) or blast % (85% vs. 80%, p=0.23) at diagnosis between patients with and without NUP98/NSD1. Mutations in NPM1 and CEBPA were not detected in those with dual FLT3/ITD and NUP98/NSD1; however, WT1 was significantly more common in FLT3/ITD patients with NUP98/NSD1 than in those without it (43% vs. 13%, p=0.01). Complete remission (CR) rates were compared in FLT3/ITD patients with and without NUP98/NSD1. CR rate in those with and without NUP98/NSD1 was 28% vs. 73% (p=0.002). Moreover, FLT3/ITD patients harboring NUP98/NSD1 were also more likely to have post-induction minimal residual disease (MRD) than those without NUP98/NSD1 (75% vs. 40.6%, p=0.03). In addition to patients with NUP98/NSD1, eight additional patients had NUP214/CAN translocation (i.e., t(6;9)), and cumulatively, translocations involving these two NUP genes accounted for 20% of patients with FLT3/ITD. CR rates in FLT3/ITD-positive patients with and without NUP translocations was determined. Those with NUP98 or NUP214 translocations had a CR rate of 40% compared to 74% in those without NUP translocations (p= 0.001). Further, the presence and prognostic significance of NUP98/NSD1 was then evaluated in CN-AML. The prevalence NUP98/NSD1 in this patient population was 7.8%. Of note, seventy-nine percent of the CN-AML patients with NUP98/NSD1 harbored FLT3/ITD as well. The CR rate for CN-AML harboring NUP98/NSD1 was significantly lower than in those without it (50% vs. 79.5%, p=0.03). When analyzing CN-AML patients who harbored both NUP98/NSD1 and FLT3/ITD, only 33% achieved CR, whereas all patients who with NUP98/NSD1 without FLT3/ITD achieved CR. Although the CR rate does not appear to be affected, AML patients with FLT3-ITD have higher relapse rates and therefore inferior outcome. We now show that among patients with FLT3/ITD, those with concurrent NUP fusions have a very low-rate of CR and high post-induction MRD than those without this fusion. The high prevalence of FLT3/ITD among NUP patients is likely not random and it is conceivable that NUP and FLT3/ITD have cooperating functional consequences that lead to a distinct leukemic phenotype and enhanced drug resistance. In conclusion, the presence of NUP in FLT3-ITD patients identifies a distinct subgroup of patients with a very high-rate of induction failure. FLT3-ITD patients should be further categorized according to the presence of NUP to improve risk-stratification of pediatric and young adult AML patients and help clinicians to identify those at very high-risk for induction failure. New therapy strategies are needed for this subgroup of patients with highly resistant disease. Disclosures: Loken: Hematologics, Inc: Employment, Equity Ownership. Pardo:Hematologics Inc: Employment.
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 | 0,001 |
| 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) | 0,002 | 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 ».