Abstract A161: A differentiation based therapeutic approach for KMT2A rearranged leukemia in infants and children
Notice bibliographique
Résumé
Abstract Introduction: Translocations in the KMT2A gene (KMT2A-r) in leukemia is an aggressive oncodriver. Currently, few therapeutic options are available for these patients and novel therapeutic strategies are urgently needed to improve outcomes. Characteristically, leukemic cells undergo a differentiation block at an early stage of development and agents that restore terminal differentiation represent an effective therapeutic strategy. Based on the initial reports that the inhibition of the Menin-KMT2A fusion is a potent inducer of leukemic cell differentiation, we sought to study a novel treatment approach to enhance the current treatment outcomes in KMT2A-r leukemia. Methods: Pediatric leukemia cells with and without KMT2A-r were studied. Differentiation was induced by the Menin inhibitor MI-463 for 12 days, followed by assessment of differentiation on day 6 and day 12 by Giemsa-Wright staining and visualization using the Infinity analyzer software. In the next set of experiments, the differentiated and undifferentiated cells were treated with common anti-leukemic chemotherapeutic agents and the induction of apoptosis and target modulation analyses were carried out by Annexin/PI staining and immunoblotting. The differentiated cells were also treated with a panel of 220 FDA approved agents, targeting diverse oncogenic pathways to generate a sensitivity signature specific to the differentiated cells. Gene expression array studies were used to identify differentially expressed genes in the two cell populations. Results: The KMT2A-r leukemia cells showed increased dose dependent sensitivity to MI-463. The highest drug sensitivity was exhibited by the infant leukemia cell line MV4-11. At 1µM, no significant loss of cell viability was noted but the rate of proliferation was significantly decreased compared to DMSO control, providing optimal conditions for differentiation. Leukemic cells cultured with MI-463 showed characteristic morphological changes of differentiation including vacuolated cytoplasm, kidney shaped nuclei and decreased nuclei to cytoplasmic ratio. Importantly, we found that the differentiated cells showed a similar chemosensitivity pattern but the sensitivity to AraC was greatly reduced. For example, in MV4-11 cells, IC50 was 170 nM compared to 8 nM in undifferentiated cells. Directed drug screen and differential gene expression studies identified specific growth and survival pathways that can be positively targeted in differentiated cells. Discussion: Data presented demonstrate the activity of MI-463 to induce cell death as well as to initiate differentiation in KMT2A-r cells. We further characterize the sensitivity profile of current chemotherapeutic agents for multi-agent treatment regimens and identify novel agents to optimize future treatment protocols. Differential gene expression analyses were used to understand the potential mechanisms of therapeutic vulnerabilities in these cells. Our results provide the first preclinical evidence to select agents and combinations to improve the outcomes in KMT2A-r leukemia in children. Citation Format: Ritul Sharma, Aru Narendran. A differentiation based therapeutic approach for KMT2A rearranged leukemia in infants and children [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A161.
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 | 0,001 |
| 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 ».