Epigenetic Therapy Inhibits NUP98-HOXA9-Mediated Myeloid Disease – Decitabine and Valproic Acid Work Synergistically to Rescue Normal Hematopoiesis in Transgenic Zebrafish.
Notice bibliographique
Résumé
Abstract Abstract 2391 Acute myeloid leukemia (AML) results from multiple genetic lesions that alter white blood cell development, leading to hyperproliferation and a block in differentiation. A better understanding of these molecular pathways will enable the development of therapies that selectively target the specific abnormality in a leukemic cell with improved outcome and limited toxicity. Pertinent animal models serve as essential intermediaries between in vitro studies and the use of these new agents in clinical trials. The NUP98-HOXA9 (NHA9) fusion oncogene is found in high risk de novo AML, treatment related AML and chronic myeloid leukemia (CML) blast crisis. We previously generated a transgenic zebrafish model overexpressing human NHA 9 under the zebrafish pu.1 promoter (Forrester et al, BJH, 2012). Almost 25% of adult NHA9-transgenic fish develop a myeloproliferative neoplasm (MPN) in the kidney marrow, the site of adult hematopoiesis. Additionally, NHA9- transgenic embryos demonstrate an increase in immature myeloid cells (l-plastin1, 2.3-fold by in situ, P<0.005) at the expense of erythroid cells (gata1, 19.3-fold by qRT-PCR, P<0.00005). This embryonic phenotype in our NHA9 zebrafish provides an unprecedented opportunity to perform in vivo screens for collaborating genes in NHA9-induced leukemogenesis and evaluate the impact of molecularly targeted agents. Microarray analysis found high expression of DNA (cytosine-5-)-methyltransferase 1 (dnmt1) in NHA9 embryos, which was confirmed by qRT-PCR (3.4-fold increase). The methylating activity of the DNMT1 enzyme is part of the epigenetic machinery that represses genes needed for terminal myeloid differentiation. Overexpression of human DNMT1 has been found in some cases of AML, but has not been previously linked with NHA9-induced disease. The overexpression of the zebrafish dnmt1 homolog in NHA9 embryos may keep cells trapped in an immature state, a hallmark of AML. Injecting NHA9 embryos with a gene-blocking dnmt1 morpholino restored normal hematopoiesis with wild-type expression levels of both l-plastin and gata1. Similarly, a dose-dependent return to normal proportions of myeloid and erythroid cells was achieved by bathing NHA9 embryos in 50–100 μM decitabine (5-aza-2'-deoxycytidine), a demethylating agent that specifically targets the DNMT1 enzyme. However, decitabine use as a monotherapy carries the risk of genomic instability due to wide-spread DNA hypomethylation. We therefore considered treating our NHA9 zebrafish embryos with combination therapy against multiple molecular targets. DNMT1 is part of a larger epigenetic machinery and works in parallel with histone deacetylation complexes (HDACs). Similar to decitabine, exposing NHA9 embryos to 150–250 μM of the HDAC inhibitor, valproic acid (VPA), lead to a dose-dependent return of normal hematopoiesis. In vitro studies suggest that combined treatment with a demethylating agent and an HDAC inhibitor may synergize to be more effective than either compound alone in combating myeloid disease, permitting use of lower drug doses, thus avoiding unnecessary toxicity. Indeed, we found that combination doses as low as 10 μM each of decitabine and VPA restored normal hematopoiesis as effectively as significantly higher doses of each monotherapy. This drug synergy identified in our transgenic zebrafish directly links NHA9-induced leukemia and epigenetic regulation and has set the stage for a new and exciting therapeutic approach for high risk AML. True to our goal, translating this treatment to clinical studies may ultimately improve outcome and minimize toxic side-effects, thereby increasing the long-term survival of patients with high-risk AML. 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 ».