Growth Factor-Dependent Activation of a MYC-Induced Latent AML Program in Human Hematopoietic Cells
Notice bibliographique
Résumé
Background: Current evidence suggests that genetic and epigenetic abnormalities drive the development of human Acute Myeloid Leukemias (AMLs). However, whether these are sufficient to establish a permanent, self-sustaining AML population, and the potential role of shared perturbed downstream pathways is unknown. We hypothesized that a modest upregulated expression of MYC might play such a role given its commonly increased expression in many AML patients' cells. To test this hypothesis, we assessed the dynamics and types of cells produced in sublethally irradiated NOD-Rag1-/--IL2Rγc-/-(NRG) mice transgenically producing human IL3, GM-CSF and SCF (NRG-3GS mice) following their transplantation with freshly isolated subsets of normal CD34+ cord blood (CB) cells that were first lentivirally transduced with a human MYC cDNA. Results: FACS and Western blot analyses indicated this produced a 2 to 5-fold increase in MYC mRNA and protein levels in MYC-transduced CD34+ CB cells, and 21/22 NRG-3GS mice injected with ≥6,500 of these cells developed a fatal human AML population within 7 weeks. Histological analysis of their bone marrow and spleen cells showed both contained a prominent human CD123+CD33+CD15±CD34-CD14-CD19-CD3- blast population. Additional limiting dilution transplants showed that both the CD34+CD38- cells (enriched for hematopoietic stem cells) and the more differentiated CD34+ GMPs were similarly highly susceptible (at frequencies of 1/14 and 1/46, respectively) and, in both cases, generated progeny that could initiate serially transplantable leukemias with the same phenotypic and transcriptomic features. Comparison to normal CB cells indicated these most closely resembled GMPs, and comparison to pediatric AML patient samples indicated a similarity to myelomonocytic leukemias with enhanced MYC expression. Interestingly, 14 sublethally irradiated NRG mice (the parental strain not producing human 3GS) transplanted with matched aliquots of CD34+ MYC-transduced cells regenerated a normal spectrum of CD19+ lymphoid cells, CD14+ and CD15+ GM cells and readily detectable CD34+ cells for up to 32 weeks of follow-up with no evidence of leukemogenesis. However, transfer of these regenerated human cells into secondary NRG-3GS mice, even after this extended period, enabled their rapid production of a lethal human AML in all 5 mice tested. In contrast, matched aliquots transplanted into 5 NRG recipients produced declining grafts of normal cells. This finding was then exploited to determine which growth factors were responsible for activating the AML program by transplanting NRG mice with CD34+ CB cells transduced with MYC and just a single growth factor, or all 3 as a positive control. In this set of experiments, a lethal human AML was obtained when MYC was paired with human IL3 or GM-CSF (or all 3 together), but not with SCF (or no growth factors). Conclusion: We report here a new in vivo model of MYC-induced human myeloid leukemogenesis that produces a serially transplantable AML closely resembling human pediatric myelomonocytic leukemias with elevated MYC expression. The rapidity, consistency, and high frequency of this transformation process obtained by transducing late granulopoietic as well as early types of normal human CD34+ progenitor cells makes this system highly attractive for future mechanistic and therapeutic testing experiments. The discovery that MYC deregulation alone generates a stable "latent program" that can be rapidly activated by exposure to exogenous growth factors typical of inflammatory states also raises intriguing questions about the potential role of such events in the genesis of AML populations that arise in patients. Disclosures Beer: Karus therapeutics Ltd.: Employment.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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) | 0,003 | 0,001 |
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 ».