Chaetocin Exhibits Anti-Leukemia Activity Against Chronic Myeloid Leukemia Stem Cells
Notice bibliographique
Résumé
Abstract Abstract 1667 Treatment of chronic myeloid leukemia (CML) patients with tyrosine kinase inhibitors (TKIs) targeting BCR-ABL kinase results in a dramatic reduction in proliferating BCR-ABL expressing leukemia cells. However, these agents do not eliminate the CML stem cell population, indicating that inhibiting BCR-ABL kinase activity alone is not sufficient to eradicate the disease, and implicating TKI-insensitive CML stem cells in relapse. Thus, there is great interest in identifying new therapeutic agents that can be combined with TKIs to eliminate TKI-insensitive CML stem cells that are not fully addicted to BCR-ABL. Chaetocin, a mycotoxin that inhibits histone methyltransferase SUV39H1, exhibits anticancer properties against myeloma and AML cells. To investigate a potential role for chaetocin in CML treatment, we first compared its cytotoxic effects with those of imatinib on TonB210, a murine hematopoietic cell line with doxycycline-inducible BCR-ABL expression that is dependent on BCR-ABL for survival and proliferation in the absence of exogenous IL-3. As expected, imatinib treatment produced cytotoxic effects in TonB210 cells induced to express BCR-ABL, but not in uninduced TonB210 cells, as assessed by trypan blue viability assays and Annexin V expression by flow cytometry. In contrast, chaetocin, displayed significant cytotoxicity against both TonB210 cells induced to express BCR-ABL and uninduced TonB210 cells. We then used a standard murine retroviral transduction system that models CML blast crisis (BC-CML) to study chaetocin effects on BCR-ABL expressing cells highly enriched for leukemia initiating potential. Purified LIN-, Sca-1+, CD117+ cells (LSKs) were isolated from the bone marrow of C57BL6/J mice and retrovirally-transduced with BCR-ABL-GFP and Nup98/HoxA9-YFP then injected intravenously into recipient C57BL6/J mice. All animals developed leukemia within 21 days characterized by leukocytosis and extensive infiltration of bone marrow and spleen with leukemic blasts. LSKs expressing both BCR-ABL-GFP and Nup98/HoxA9-YFP (GFP+/YFP+ LSKs) were purified from the spleens or bone marrows of leukemic mice and cultured for 48 hrs in chaetocin across a range of concentrations (0 – 400 nM). Chaetocin exhibited cytotoxic effects against GFP+/YFP+ LSKs as assessed by trypan blue, Annexin V, and colony forming assays. Chaetocin effects on CML stem cell self-renewal in vivo were assessed by performing secondary transplantation assays and limiting dilution analysis (LDA). GFP+/YFP+ LSKs were purified from primary CML mice and transplanted into secondary recipients following in vitro exposure to IC50 concentrations of chaetocin and/or imatinib. Survival after transplantation and LSC frequency were compared in four treatment cohorts: Group 1 (untreated control), Group 2 (chaetocin), Group 3 (imatinib) and Group 4 (chaetocin + imatinib). Compared to untreated mice, survival was significantly prolonged in mice treated with imatinib alone and the survival benefit of imatinib was enhanced by co-treatment with chaetocin. LDA showed both chaetocin and imatinib treatment alone decreased LSC frequency (1 in 10,143 in chaetocin treated, and 1 in 95,782 in imatinib treated vs. 1 in 4,036 in untreated control) but that the combination of chaetocin and imatinib treatment resulted in a dramatic decrease in LSC frequency (1 in 293,628 in chaetocin + imatinib treatment vs. 1 in 4036 in untreated control). Chaetocin, imatinib, and chaetocin + imatinib treatment of normal murine hematopoietic stem cells resulted in only minimal cytotoxicity as assessed by trypan blue, Annexin V, and colony forming assays. Our findings suggest that chaetocin, or chaetocin-related compounds, might serve to complement TKI therapy in the treatment of CML. 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 | 0,000 |
| 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 ».