Identification of Novel Antigens for Normal Karyotype Triple Mutated Acute Myeloid Leukemia
Notice bibliographique
Résumé
Introduction Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. AML is divided in several subgroups based on genetic alterations and prognosis varies among AML subgroups. Normal karyotype AML with NPM1, DNMT3A and FLT3(ITD) mutations (NK triple mutated AML) is associated with a long-term overall survival of ~20% and represents ~6% of AML cases (Papaemmanuil et al., NEJM, 2016). No curative chemotherapy for this subgroup of AML patients currently exists, highlighting the need to develop novel therapeutic strategies for this group of AML patients. Methods To identify novel cell surface antigens for NK triple mutated AML that could ultimately be targeted by immunotherapeutic approaches, we developed a method to map the surface proteome of primary human AML specimens based on biotinylation of cell surface proteins, affinity purification and mass spectrometry. To further enrich mass spectrometry datasets with surface proteins, we developed an algorithm that assesses the probability of a protein to be located on the cell surface based on annotations from various databases. Using this approach, the surface proteome of 100 primary human AML specimens was analysed, which included 12 NK triple mutated AML samples. Differential surfaceome analyses identified several surface proteins specifically expressed by NK triple mutated AML specimens. Expression analyses were performed using publicly available datasets to select proteins with limited expression in normal tissues and hematopoietic cells. Surface expression and AML subgroup specificity for these potential antigens was evaluated by flow cytometry using primary human AML specimens from various AML subgroups (n=76). Moreover, to assess the intra-specimen expression profile of these antigens, single cell RNA-sequencing of 15 primary human NK triple mutated AML specimens was performed. Finally, we evaluated the prognostic impact of antigen expression on overall survival in a subgroup of patients from the Leucegene cohort composed of patients diagnosed with de novo AML with intermediate risk cytogenetics who have been treated with intensive induction chemotherapy (n = 316). Results Surface proteome analysis of NK triple mutated AML specimens and hit filtering according to selection pipeline described above identified several promising NK triple mutated AML antigens. Surface expression analysis of these antigens by flow cytometry showed specificity of antigen expression for NK triple mutated AML specimens. Transcriptomic analyses using RNA sequencing data from primary human AML specimens of the Leucegene cohort (n=691) showed significantly higher antigen transcript levels in NK triple mutated AML specimens compared to samples from other AML subgroups. Moreover, multivariate transcriptome analysis comparing the impact of most frequent mutations in AML on antigen expression revealed that FLT3-ITD mutation is the only significant factor associated with antigen overexpression in AML samples. Single cell RNA sequencing data from NK triple mutated AML specimens revealed that these antigens are uniformly expressed across the vast majority of blast populations, including blast cells with an expression profile reminiscent of leukemic stem cells. Interestingly, in patients with intermediate cytogenetic risk AML, high antigen expression was significantly associated with worse overall survival. Patients with high antigen expression who proceeded to allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission also had a significantly lower 5-year overall survival rate post-HSCT compared to patients with low antigen expression. Conclusion We identified novel antigens for FLT3-ITD mutated and NK triple mutated AML, which show homogeneous expression in blast populations of AML samples including most primitive ones, making it ideal antigens for immunotherapeutic targeting. Patients with intermediate cytogenetic risk AML and high antigen expression show poor prognosis even after HSCT in first complete remission, highlighting the need to develop novel therapeutic strategies for these patients. Different immunotherapeutic approaches targeting these antigens are currently being developed by our group, with the hope of identifying novel therapeutic strategies for the treatment of NK triple mutated AML.
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 | 0,001 | 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 | 0,001 |
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 ».