Aldehyde Dehydrogenases Play a Role in Acute Myeloid Leukemia and Have Prognostic and Therapeutic Significance
Notice bibliographique
Résumé
Abstract Aldehyde dehydrogenase 1A1 (ALDH1A1) is highly expressed in CD34+ hematopoietic stem cells (HSCs) and functions in part to metabolize ROS and reactive aldehydes, important functions for maintaining the stem cell compartment. In this study we examined the role of ALDH isoforms in acute leukemia. We report here that loss of ALDH1A1, along with a compensatory isoform ALDH3A1, predisposes to acute leukemia in a murine model. Further, approximately 25% of human AMLs were also found to express low levels of ALDH1A1 and ALDH3A1 and this subset has a better outcome to treatment with standard AML therapies. A number of other ALDH isoforms are expressed in AML and higher levels of ALDH7A1 expression correlated with better outcomes particularly when this marker is combined with low-level ALDH1A1 expression. Kasumi-1, a model human ALDH1A1-/3A1- AML cell line, was found to have high levels of intracellular ROS, reactive aldehydes and DNA damage all of which were ameliorated by ALDH1A1 re-expression using lentiviral vector gene transfer. To analyze the variability of ALDH1A1 expression noted in the gene expression studies, 20 primary AML samples were stained with Aldefluor, a fluorescent substrate for ALDH1A1 along with CD34 and CD38 and analyzed by flow cytometry. This revealed further heterogeneity in ALDH activity with 25% of samples having no cells detectable by Aldefluor staining (termed ALDH1A1- AML) and 75% having variable proportions of cells with Aldefluor staining which we grouped into ALDH1A1Low (0.1-1.5% Aldefluor+ cells), ALDH1A1Intermediate (1.6-10% ALDH+ cells) and ALDH1A1high (>10% ALDH+ cells) AMLs. Both Kasumi-1 and ALDH1A1-/3A1- primary AML samples, compared to their ALDH+ counterparts, were highly sensitive to toxic ALDH substrates including 4-HNE and Cyclophosphamide (Cy) and the effects of Cy were potentiated by treatment with Arsenic Trioxide (ATO), and parthenolide (PTL). Similar results were seen when ALDH- and ALDH+ AML cells from the same sample were sorted to purity and treated with 4-HC+ATO. In contrast, normal CD34+ cells were relatively resistant to these agents. Lastly, ALDH3B1 was found to be elevated in many AML samples which had low or absent levels of ALDH1A1 suggesting it may compensate for loss of ALDH1A1 and inhibition of ALDH3B1 also potentiated the toxic effects of Cy and other agents. Together these results demonstrate that several of the ALDHs play an important role in leukemia, expression levels of individual isoforms have important prognostic significance and the absence of the ALDH1A1 isoform in a subset of leukemias may allow the application of targeted therapies that exploit this difference with normal HSCs. Based on our laboratory findings, we propose a clinical study in which AML patients with low/negative ALDH1A1 will be treated with a regimen combining Cy and ATO. 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 | 0,001 | 0,001 |
| 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) | 0,001 | 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 ».