High-Level IGF1R Expression Is Required for Leukemia Stem Cell Activity In T-ALL and Is Supported by Notch Signaling.
Notice bibliographique
Résumé
Abstract Abstract 3649 T-cell acute lymphoblastic leukemia (T-ALL) is a lethal cancer of immature T cells that often shows aberrant activation of NOTCH1 and PI3K/Akt pathways. Although PI3K/Akt signaling is potentiated by PTEN mutations which occur in up to 20% of cases, upstream signals which initiate PI3K/Akt activation remain unclear. IGF1R is a receptor tyrosine kinase upstream of PI3K/Akt and Ras/Raf/MAPK signaling pathways with known roles in cancer cell growth and is expressed broadly in primary human T-ALL cells and established cell lines. We thus considered that IGF1R may represent a biologically relevant upstream activator of the PI3K/Akt pathway in T-ALL. Consistent with this idea, we demonstrate that treatment of human and mouse T-ALL cells with small molecule IGF1R kinase inhibitors and IGF1R blocking antibodies resulted in growth arrest of bulk cells. As well, genetic deletion of IGF1R by inducible Cre expression in mouse T-cell leukemias also leads to growth arrest and apoptosis of bulk cells. IGF1R and PI3K/Akt/mTOR signaling have also been described to promote self-renewal of normal and cancer stem cells, and thus we addressed whether IGF1R may play a role in leukemia stem cell (LSC) activity in T-ALL. Since outgrowth of bulk leukemia cells is required to detect LSC activity in vivo, we were not able to address IGF1R function in LSCs by genetic deletion; however, we elected to take advantage of a well-characterized hypomorphic allele of IGF1R carrying an integrated neo cassette within the second intron. IGF1Rneo/neo mice express full-length IGF1R protein, but at reduced levels (30-60% of wild-type). Despite this reduced expression level, we were able to generate lethal T-cell leukemias with 100% penetrance in primary recipients of IGF1Rneo/neo bone marrow transduced with activated NOTCH1 retrovirus, similar to what is observed with IGF1R+/+ bone marrow. Upon IV or intra-medullary injection into secondary congenic recipients, however, IGF1Rneo/neo leukemias exhibited a striking transplantation defect. Whereas IGF1R+/+ leukemias are consistently serially transplantable, 5 of 16 primary IGF1Rneo/neo leukemias failed to reconstitute disease in any secondary recipients, 5 produced disease in only a subset of secondary recipients, and 6 produced disease in all secondary recipients. Furthermore, treatment of IGF1R+/+ leukemia cells in vitro with IGF1R inhibitor prior to injection into secondary recipients prevented their transplantability, whereas treatment with PI3K and ERK inhibitors did not. Finally, given that inhibition of Notch signaling in human T-ALL cells compromises their ability to recapitulate disease in NOD/Scid recipients, we wondered whether this effect could be mediated by downregulation of IGF1R. In fact, we observed inhibition of Notch signaling, either by small molecule gamma-secretase inhibitor or transduction with dominant negative Mastermind, to result in a 2–3 fold decrease in IGF1R protein expression, corresponding to a 5 to 20-fold decrease in response to stimulation by IGF-1 ligand. Thus, these studies demonstrate high-level IGF1R signaling is required for LSC activity in T-ALL, and that Notch signaling may promote LSC function by supporting IGF1R expression. IGF1R inhibitors may therefore prove clinically useful in preventing disease relapse by compromising LSC self-renewal. Disclosures: Carboni: Bristol-Myers Squibb: Employment. Gottardis:Bristol-Myers Squibb: Employment.
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) | 0,003 | 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 ».