Chaetocin Anti-Leukemia Activity Against Chronic Myelogenous Leukemia Stem Cells Is Potentiated By Bone Marrow Stromal Factors and Overcomes Innate Imatinib Resistance
Notice bibliographique
Résumé
Abstract Chronic myelogenous leukemia (CML) is maintained by a minor population of leukemic stem cells (LSCs) that exhibit innate resistance to tyrosine kinase inhibitors (TKIs) targeting BCR-ABL. Innate resistance can be induced by cytokines and growth factors secreted by bone marrow stromal cells (BMSFs) that protect CML-LSCs from TKIs, resulting in minimal residual disease. Developing therapies that can be combined with TKIs to eradicate TKI-insensitive CML-LSCs, is critical for disrupting innate TKI resistance and preventing disease relapse. Cancer cells balance reactive oxygen species (ROS) and antioxidants at higher than normal levels, which promotes their proliferation and survival, but also makes them susceptible to damage by ROS-generating agents. BCR-ABL expression increases cellular ROS levels, whereas, TKI inhibition of BCR–ABL reduces ROS. Furthermore, BMSFs, which are implicated in innate TKI resistance, can increase ROS levels in CML cells. Thus, we postulated that BMSF mediated increases in ROS might enhance triggering of ROS-mediated damage in TKI treated CML-LSCs by chaetocin, a mycotoxin with anticancer properties that imposes oxidative stress by inhibiting thioredoxin reductase-1. To investigate chaetocin effects on innate TKI resistance, we first compared its activity with imatinib against TonB210, a murine hematopoietic cell line with inducible BCR-ABL expression, in response to BMSFs. Imatinib did not affect the growth of BCR-ABL(-) TonB210 cells but suppressed BCR-ABL(+) Ton-B210 growth, and BMSFs protected against imatinib growth suppression. In contrast, chaetocin significantly suppressed the growth of both BCR-ABL(-) and BCR-ABL(+) TonB210 cells, and these effects were potentiated by BMSFs. We then compared the effects of chaetocin as a single agent, and in combination with imatinib, on the growth of CML-LSCs derived from an established murine retroviral transduction/transplantation model of CML blast crisis, in response to BMSFs. The presence of BMSFs reduced cytotoxicity and apoptosis induction by imatinib, but potentiated these effects in chaetocin treated CML-LSCs. Colony formation by CML-LSCs was significantly inhibited by treatment with either imatinib or chaetocin. However, BMSFs conferred significant protection from colony inhibition by imatinib, whereas, no colony formation was observed in cells exposed to chaetocin and BMSFs. Both BMSFs and chaetocin increased ROS in CML-LSCs and the addition of BMSFs and chaetocin resulted in significantly higher levels compared to chaetocin or BMSFs alone. Pretreatment of CML-LSCs with the anti-oxidant N-acetyl-cysteine blocked chaetocin cytotoxicity, even in the presence of BMSFs. Chaetocin effects on CML-LSC self-renewal in vivo were assessed by transplanting CML-LSCs into secondary recipients following in vitro exposure to chaetocin, in the presence or absence of BMSFs. Disease latency in mice transplanted with CML-LSCs following chaetocin treatment more than doubled compared to mice transplanted with untreated CML-LSCs or CML-LSCs exposed to BMSFs. Mice transplanted with CML-LSCs following chaetocin treatment in the presence of BMSFs had significantly extended survival time compared to mice transplanted with CML-LSCs treated with chaetocin alone. Our findings indicate that chaetocin activity against leukemia initiating cells is significantly enhanced in the presence of BMSFs and suggest that chaetocin may be effective as a co-drug to complement TKIs in CML treatment by disrupting the innate resistance of CML-LSCs through an ROS dependent mechanism. Disclosures No relevant conflicts of interest to declare.
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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 ».