Disease Stage Strongly Modulates Responsiveness to Targeted Agents in Nf1 Mutant Mice with Myeloprolfierative Disease (MPD) and Acute Myeloid Leukemia (AML).
Notice bibliographique
Résumé
Abstract Hyperactive Ras is a biochemical abnormality in many cases of myelodysplastic syndrome (MDS), MPD, and AML. The genetic mechanisms that deregulate Ras signaling in myeloid malignancies include NRAS, KRAS2, and PTPN11 point mutations, FLT3 internal tandem duplications, and inactivation of the NF1 tumor suppressor. Inactivating Nf1 or expressing an oncogenic allele of Kras2 in murine hematopoietic cells induces MPD with 100% penetrance; however, this does not evolve to AML. We exploited retroviral insertional mutagenesis to induce mutations that might cooperate with Nf1 inactivation in myeloid leukemogensis. In these studies, Mx1-Cre, Nf1flox/flox and control pups were injected with the MOL4070A retrovirus (Wolff, et al. J Virol 2003) and with pIpC to induce Cre recombinase expression and thereby inactivate Nf1. Approximately 25% of the Mx1-Cre, Nf1flox/flox mice developed AML. The Ras effectors MEK and ERK were hyper-phosphorylated in these AMLs. We next compared the effects of CI-1040, a highly selective inhibitor of the MEK kinase, on colony growth in methylcellulose of Nf1 mutant cells from mice with MPD and AML. Importantly, there was no differential sensitivity of the MPD mutant cells to CI-1040 as CFU-GM colony formation from Mx1-Cre, Nf1flox/flox and wild-type bone marrow was inhibited at the same drug dose. By contrast, colony formation of AML Mx1-Cre, Nf1flox/flox cells was abrogated at much lower CI-1040 concentrations. A randomized trial of CI-1040 in Mx1-Cre, Nf1flox/flox MPD model (n=10) at the maximal tolerated dose of 100mg/kg twice a day showed no improvement in leukocyte counts, splenomegaly, or survival in Nf1 mutant mice with MPD. We demonstrated transient inhibition of the ability of GM-CSF to phsophorylate ERK in primary bone marrow cells from CI-1040-treated mice. Whereas ERK phosphorylation was markedly decreased 2 hours following a CI-1040 dose, inhibition was marginal at 4 hours and absent by 8 hours. Based on the increased in vitro sensitivity of Mx1-Cre, Nf1flox/flox AML cells to CI-1040, we performed a second randomized trial in 25 recipient mice that were transplanted with 4 independent leukemias. CI-1040 had dramatic effects in this setting. Whereas the leukocyte counts of vehicle-treated mice increased progressively, we observed a transient fall in leukocyte counts in all mice randomized to receive CI-1040. Treatment with CI-1040 was also associated with markedly prolonged survival (24 versus 7 days in the vehicle-treated cohort; odds ratio 3.5 95% CI 3.0–3.8). These data demonstrate that the biologic response to a molecularly-targeted inhibitor is strongly modulated by the genetic context in which a disease-initiating mutation occurs. Specifically, although the MPD induced by Nf1 inactivation was resistant to CI-1040, progression to AML was associated with enhanced sensitivity to this agent. Our data support further clinical development of MEK inhibitors with better pharmacologic characteristics as a rational strategy for treating advanced myeloid malignancies. This mouse model also provides a tractable system for identifying cooperating mutations that cause progression to AML and modulate drug sensitivity.
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 | 0,001 |
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 ».