PF204 TARP AS IMMUNOTHERAPEUTIC TARGET IN AML EXPRESSED IN THE LSC COMPARTMENT
Notice bibliographique
Résumé
Background: Acute myeloid leukemia (AML) accounts for 80% of adult and 20% of pediatric leukemias. Despite frequent initial remission, patients exhibit a high relapse risk, probably due to therapy‐resistant leukemic stem cells (LSCs). Particularly the prognosis of FLT3‐ITD harboring patients remains extremely poor. Aims: To identify LSC‐specific targets and develop immunotherapeutic strategies for LSC elimination while assuring salvage of normal hematopoietic stem cells (HSCs). Methods: The GSE 17054 micro‐array dataset was used for transcriptome analysis of CD34+CD38‐ populations sorted from de novo adult AML (LSCs, n = 9) and healthy adults (HSCs, n = 4). We next evaluated transcript expression in CD34+CD38‐ and CD34+CD38+ populations sorted from de novo pediatric AML (pedAML) and healthy controls. An 8x60K human gene expression micro‐array was performed in four pediatric AML (pedAML) (2 FLT3 WT, 2 FLT3‐ITD) and 3 cord blood samples. In addition, qPCR was performed in 13 pedAML, 17 adult AML, and 15 controls (cord blood, normal bone marrow and mobilized blood stem cells). Finally, cell lines of various origin, including 9 AML cell lines, were examined. Protein expression was evaluated by Western blotting and confocal microscopy. Viral transduction was used to generate T‐cell receptor (TCR)‐engineered cytotoxic T‐cells (CTLs), next to HLA‐A ∗ 0201 expressing, TARP overexpression and TARP knockdown AML cell lines. Killing by TCR‐engineered CTLs was evaluated in vitro by cytokine assays, flow cytometry‐ and bioluminescence‐based killing assays. Results: Re‐analysis of the GSE 17054 dataset revealed that the TCRγ chain alternate reading frame protein (TARP) was the most differentially expressed gene between LSC and HSC. Until now, TARP is known as a prostate‐specific marker, also expressed in breast adenocarcinoma. Subsequently, micro‐array and qPCR analysis showed aberrantly high TARP expression within pedAML and adult AML leukemic blasts and LSCs, while absent in normal counterparts. Noteworthy, all FLT3‐ITD harboring pedAML patients (n = 8) showed high TARP expression (P < 0.01), whereas this association was not significant for FLT3‐ITD adult AML (n = 9). No TARP transcripts were identified in B‐ALL, CML nor B‐cell lines, while expression in AML cell lines was significantly higher (P < 0.001). Aberrant TARP expression in cell lines and primary patient samples was confirmed at the protein level and confocal microscopy further corroborated these data. Importantly, cell lines and primary patient samples co‐expressing TARP and HLA‐A ∗ 0201 were efficiently killed by TARP‐TCR engineered CTLs, providing proof‐of‐concept that TARP qualifies as a physiologically relevant target for T‐cell therapy in AML. Summary/Conclusion: We showed that TARP is highly expressed in AML leukemic cells, including LSCs, while absent in normal counterparts. High TARP expression is significantly associated with FLT3‐ITD in pedAML, a marker for poor prognosis. TARP‐TCR engineered CTLs effectively killed TARP+ HLA‐A ∗ 0201+ co‐expressing AML cell lines and primary leukemic cells in vitro . To the best of our knowledge, this is the first report indicating that TARP‐TCR engineered CTLs hold great promise for immunotherapeutic T‐cell therapy in 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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 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) | 0,031 | 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; les deux têtes enseignantes s’accordent sur ce qui est montré ici.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».