Leukemic Stem Cell Expression Signatures Identify Novel Therapeutics for Acute Myeloid Leukemia
Notice bibliographique
Résumé
Abstract Acute myeloid leukemia (AML) has a relatively poor 5-year survival rate of 30% in adults, largely due to high rates of relapse, which is thought to be driven by chemoresistant leukemic stem cells (LSCs). A therapy would need to eradicate all LSCs to obtain durable responses in AML patients. Unlike typical cancerous cells, LSCs are often quiescent, allowing them to evade standard therapies and serve as a reservoir for relapse. Thus, the identification of novel anti-LSC therapies could result in the improvement of the clinical outcome of patients suffering from AML. To identify compounds predicted to impede LSC function while not affecting normal hematopoietic stem cells (HSCs), we probed datasets of drug-gene interaction with our previously defined LSC and HSC gene expression signatures generated from 16 primary AML samples and 4 pooled cord blood samples (Eppert et al. Nat Med, 2011), and an additional LSC-signature from 86 AML patients (unpublished data; Ng et al. Nature, 2016). We identified 152 molecules predicted to target LSCs without harming HSCs. Eighty-three of these molecules were screened against a primary AML sample (8227) with a known LSC-containing population (confirmed as CD34+CD38- by xenotransplantation). Viability and phenotype were assessed by flow cytometry. We identified multiple hits in two classes of drugs: 3 drugs in a subclass of steroids and 3 drugs in a specific group of ion pump inhibitors, that preferentially eliminated CD34+CD38- cells over CD15+ blast cells in 8227. Many of these candidates are already in use for other clinical settings. The steroids induced differentiation in the lower nanomolar range (IC50: 0.44-1.30nM), shown by a depletion of primitive CD34+CD38- cells and subsequent expansion of terminally differentiated CD15+ cells. The ion pump inhibitors preferentially targeted the CD34+CD38- cells (IC50 CD34+CD38-: 11.55nM, 24.69nM, 21.78nM) over the CD15+ blast cells (IC50 CD15+: 17.72nM, 32.73nM, 45.09nM). To determine the toxicity of our candidates towards normal stem and progenitor blood cells, we exposed CD34+ enriched human cord blood to the steroids and ion pump inhibitors. All candidates had minimal effects against the CD34+ cord blood cells compared to CD34+ 8227 cells. We then tested the compounds against multiple primary AML samples and observed that at low nanomolar concentrations (0.3-4.0nM) the steroids differentiated AML #9642 (M4e, NPM1-WT, FLT3-WT) but had no effect on AML #9706 (M1, NPM1-WT, FLT3-ITD). For the ion pump inhibitors, AML #184 (M4, NPM1-MT, FLT3-TKD) and AML #9642 were sensitive while AML #116 (M0, NPM1-WT, FLT3-WT) and AML #9706 were more resistant. This variability in sensitivity to both groups of candidates suggests a possible link to subtype or genotype to responsiveness. To evaluate the effect of the steroids and ion pump inhibitors on functional leukemic progenitor cells, 8227 cells were treated with the steroids, ion pump inhibitors or control (DMSO) and then assessed by colony formation unit assay. Treatment with the steroids or ion pump inhibitors resulted in a 2-fold decrease in progenitors (colony formation) compared to DMSO. Next, we will expose a panel of AML patient samples to the candidate compounds in vitro to further elucidate whether there is a link between certain clinical or genotypic features and responsiveness. We will also perform xenotransplantation of treated AML samples into immunodeficient mice to assess the effects on functional LSCs. Overall, we have shown that both the subclass of steroids and specific ion pump inhibitors identified by our bioinformatic approach have anti-AML and anti-LSC properties against particular AML samples in vitro . Future results from our study will provide valuable insight to LSC biology and can lead to new therapeutic approaches for targeting the LSCs, the root of therapy resistance and relapse in AML. Disclosures No relevant conflicts of interest to declare.
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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 ».