Independent and Converging Pathways in Leukemia Stem Cells.
Notice bibliographique
Résumé
Abstract Leukemias are considered hierarchically organized where a leukemia stem cell (LSC) maintains the disease, can reinitiate disease upon transplantation, and gives rise to more mature cells which can not establish the disease after secondary transplantation. While LSCs become the primary focus for targeted therapies, little is known about the pathways regulating LSC activity. Overexpression of HOX genes characterize the large group of acute myeloid leukemia (AML) patients with NPM1 mutations whereas overexpression of MN1 is highly correlated with wildtype-NPM1 AML (Verhaak et al. 2005). We hypothesized that the LSCs in these two AML populations are differentially regulated as patients with NPM1 mutations tend to have better outcomes. To test this hypothesis we applied a transplantation model using murine bone marrow (BM) cells retrovirally transduced with MN1 or MN1+NUP98HOXD13 (ND13). Overexpression of ND13 in mouse BM leads to a “preleukemic” or MDS-like phenotype. In contrast, previously we found that overexpression of MN1 is alone sufficient to induce AML. MN1-induced leukemias were compared to MN1+ND13-induced leukemias. Mice transplanted with 1x10E6 BM cells overexpressing either MN1 or MN1+ND13 died after a median latency of 35 and 40 days, respectively (P=0.26). However, in limiting-dilution analysis of MN1 expressing cells the frequency of leukemia-stem cells (LSC) was 1 in 5465 and 1 in 3411 (two independent experiments, 0.024 percent of total cells), whereas it was 34-fold increased in MN1+ND13 coexpressing cells (0.82 percent of total cells, mean of two independent experiments; the 95 percent CIs do not overlap suggesting a significant difference). In addition, the disease latencies at limiting dilution differed significantly (MN1: 82 vs. MN1+ND13: 44 days, P=0.009), demonstrating that the addition of ND13 to MN1 enhanced the potency of the individual LSC besides its frequency. Addition of ND13 to MN1 changed the leukemic phenotype towards characteristics associated with ND13. To better understand non-redundant and redundant downstream pathways expression of several genes reportedly involved in stem-cell regulation and of HOXA and HOXB genes was quantified by qRT-PCR in MN1, ND13, or MN1+ND13 expressing cells and compared to their expression in normal BM cells. Increased expression of Bmi-1, mel18, HoxA11, and HoxB6 was observed in MN1 cells compared to normal BM. Increased expression in ND13 cells compared to normal BM were found for HoxA3, HoxA7, HoxB5, HoxB7, and HoxB8, whereas HoxA9, HoxA10, and Gata-2 showed increased expression compared to normal BM for both genes. Other important stem cell regulators like Notch1 (MN1, ND13) and HoxB4 (MN1) were expressed at lower levels than in normal BM. In summary, functional and gene expression data suggest activation of non-redundant (and redundant) pathways in MN1 compared to HOX-mediated leukemias. By modulating the LSC activity we show that addition of ND13 to MN1 has a pronounced effect on the frequency and activity of LSCs and that more aggressive LSCs are obtained by dysregulation of an additional/independent pathway. This suggests that elimination of LSCs in aggressive leukemias may require inhibition of multiple pathways.
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) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,002 | 0,001 |
| Science ouverte | 0,000 | 0,002 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,011 | 0,004 |
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 ».