A Potent Stimulator of Self-Renewal in Combination with MEIS1 Overexpression Allows the Transformation of Late Committed Myeloid Progenitors.
Notice bibliographique
Résumé
Abstract Abstract 1434 Poster Board I-457 Which cells are susceptible to leukemic transformation and which cellular properties need to be altered to cause transformation are critical issues in the understanding of leukemogenesis. We have identified that the engineered fusion gene between NUP98 and the homeodomain of HOXA10 (NA10hd) exhibits an extraordinary capacity to induce stem cell self-renewal in vitro without blocking differentiation in vivo and without having any detectable leukemogenic activity on its own. However, NA10hd induces rapid-onset leukemia in mice when it is co-expressed with Meis1. We have exploited this unique combination of defined factors to investigate the role of reactivation/intensification of the self-renewal program in leukemic transformation by assessing whether committed myeloid progenitors with essentially no intrinsic self-renewal activity can be transformed into cells with “stem-cell” like characteristics that drive leukemia. Populations enriched for hematopoietic stem cells (lin-Sca1+ckit+), common myeloid progenitors (lin-Sca1-ckit+CD34+CD16/32lo, CMP) and granulocyte-monocyte progenitors (lin-Sca1-ckit+CD34+CD16/32hi, GMP) were sorted from mouse bone marrow. Expression of NA10hd and Meis1 was achieved by retroviral transduction with MSCV based vectors carrying cassettes for NA10hd-IRES-GFP or Meis1-IRES-YFP. Transduced cells were assessed for colony formation (CFC assay) and transplanted into irradiated recipients to assess their potential to give rise to leukemia. We first temporally dissociated the potential stimulation of self-renewal by NA10hd as a “first hit” from Meis1 overexpression as a “second hit” by using bulk bone marrow cells or highly purified CMP and GMP from mice previously reconstituted with NA10hd-transduced stem cells. At the time of harvest, mice were healthy and progenitor populations from these mice showed a regular distribution and a limited replating potential. However, upon infection with Meis1 a sustained replating potential over multiple CFC rounds was induced. NA10hd-expressing CMP and GMP transduced with Meis1 also gave rise to rapid onset and aggressive AML (median latency of 46.5 days for bulk, 54 days for CMP and 92 days for GMP respectively) when transplanted into irradiated recipients. To further assess whether NA10hd plus Meis1 were sufficient for transformation of later progenitors, CMP and GMP were isolated from wildtype, normal mice and cotransduced with NA10hd and Meis. To minimize the chance of contamination of fractions, infections were also carried out with purified cells at limiting number (50 cells per culture). Neither CMP nor GMP transduced with NA10hd alone gave rise to significant engraftment and both were non-leukemogenic. In contrast, both CMP and GMP co-transduced with NA10hd and Meis1 gave rapid onset leukemia. Leukemias derived from CMP and GMP showed no obvious differences with respect to morphology, immunophenotype or capability to give rise to secondary transplants. However, there was an apparent small diminution in the potency of GMP to give rise to leukemias as indicated by slightly longer latency and incomplete penetrance (3/7 mice surviving with transduced bulk GMP). We conclude that late committed myeloid progenitor cells can give rise to leukemia in our model system and that reactivation of self-renewal potential appears to be a critical step in this transformation process. This novel model of leukemia induction now opens up possibilities to dissect the molecular mechanism by which transformation of differentiated progenitors can occur. Disclosures No relevant conflicts of interest to declare.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| 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) | 0,000 | 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 tête enseignante, 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 ».