Abstract 1509: RUNX1 dosage dictates gene signature and <i>in vitro</i> response to glucocorticoids in acute myeloid leukemia
Notice bibliographique
Résumé
Abstract Background: Poor prognosis subgroups of Acute Myeloid Leukemia (AML), such as RUNX1-mutated (RUNX1mut) AML, would greatly benefit from more efficacious therapies that target leukemic stem cells (LSC) and improve patient outcome. To understand factors that predict sensitivity to drugs, we used a chemogenomic approach to interrogate primary AML specimens. Methods: We performed RNA sequencing of 415 primary AML specimens comprising various cytogenetic subgroups. Using culture conditions that support LSC activity ex vivo, we carried out a viability screen including 20 primary AML specimens and ~5,100 low molecular weight compounds. RUNX1mut specimens showed increased sensitivity to glucocorticoid compounds (GCs). Validation screens were done in 248 primary AML samples and 32 AML cell lines treated with selected GCs in a dose-response manner. The effect of RUNX1 dosage in the in vitro response to drugs was assessed by shRNA gene knockdown. GCs target, the glucocorticoid receptor (GR), was validated by chemical blockage and shRNA silencing. Results: RUNX1mut specimens were associated with older age, French-American-British (FAB) M0 morphology, intermediate-risk cytogenetics with abnormal karyotype and poor patient survival. RUNX1mut gene expression signature showed the overexpression of previously described genes such as DNTT, BAALC and CD34, as well as novel genes such as PROM1 and EGFEM1P. Most interestingly, the expression levels of these genes was influenced by the nature of the RUNX1 mutations, with levels progressively increasing with mutations corresponding to decreased levels of functional RUNX1. Chemical screens comprising 33 RUNX1mut specimens confirmed that RUNX1mut are more sensitive to GCs than RUNX1 wild-type samples. In agreement with the RUNX1mut gene signature, the anti-proliferative effect of GCs anti-correlated with levels of functional RUNX1. Specimens harboring loss-of-function and dominant-negative RUNX1 mutations showed increased sensitivity to GCs when compared to samples carrying missense mutations expected to have little impact on RUNX1 function. Mutations in other genes, such as CEBPA and SRSF2, had an additive effect on GC sensitivity when combined with RUNX1 mutations. In accordance with our hypothesis, the downregulation of RUNX1 could reverse GC-resistance in AML cell lines, and the sensitivity to compounds was proportional to knockdown levels. Treatment of cell lines with the GR antagonist RU486 blocked the inhibitory response induced by GCs and GR silencing completely abrogated the anti-proliferative effects of GCs in GC-sensitive cells, confirming that GC operate through the GR in AML. Conclusion: Altogether, these findings highlight the impact of RUNX1 dosage on gene expression and GCs sensitivity in AML cells in vitro. Further studies should investigate the benefits of repositioning GCs in the treatment of RUNX1mut AML patients. Citation Format: Laura Simon, Vincent-Philippe Lavallée, Marie-Eve Bordeleau, Jana Krosl, Irène Baccelli, Geneviève Boucher, Bernhard Lehnertz, Tara MacRae, Réjean Ruel, Sébastien Lemieux, Anne Marinier, Josée Hébert, Guy Sauvageau. RUNX1 dosage dictates gene signature and in vitro response to glucocorticoids in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1509. doi:10.1158/1538-7445.AM2017-1509
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 | 0,000 |
| 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 ».