Noggin Overexpression Enhances Leukemic Progenitors Self-Renewal in AML by Abrogating the BMP Pathway Activation.
Notice bibliographique
Résumé
Abstract Noggin, encoded by Nog gene, is a secreted protein that inhibits the bone morphogenetic proteins (BMPs). BMPs regulate the proliferation and differentiation of many tissues, including bone, kidney and hematopoiesis, mainly through phosporylation of SMAD1, 5 or 8 . By cDNA-RDA, we found overexpression of Nog in OCI-AML2 and OCI-AML5 cell lines compared to normal bone marrow (NBM). To confirm this overexpression, we performed real-time RT-PCR on 6 NBM, 2 NBM CD34+ cells, 6 AML cell lines (OCI-AML1-5 and NB4) and 53 AML patients’ (pts) samples. NBM had very low Nog/GAPDH (Median: 1.63 X 10−5, range: 1.55 X 10−5-1.75 X 10−5). Similar levels were found in CD34+ cells. Five cells lines (OCI-AML-1, -2, -4, -5 and NB4) showed high Nog/GAPDH (range: 7.5 X 10−4 - 4.3 X 10−3), whereas OCI-AML3 expessed very low level (8.6 X 10−7). High Nog expression (>4-fold NBM level) was, also, found in 51/53 pts (96%), with a median 45.8-fold NBM level. Protein study revealed a positive correlation between Noggin and Nog RNA levels. In contrast, there was a negative correlation between Noggin and phosphorylated SMAD1, 5, 8, suggesting that Noggin plays a key role in the BMP pathway regulation in hematopoietic tissues. To analyze the effect of Noggin on leukemic behavior, we assessed the effect of Noggin on the clonogenicity of OCI-AML3. OCI/AML-3 cultured with Noggin showed enhanced plating efficiency (56±7 vs 33±6, p=0.005), increased colony size and more compact colonies. To determine whether this higher efficiency is due to enhanced leukemic progenitors self-renewal, cells were grown in suspension culture in the presence of Noggin, washed and plated in methylcellulose medium without Noggin on days 1–3. Cells treated with Noggin showed increasing colony-forming potential with time, suggesting an enhancement of leukemic progenitors self-renewal. To further characterize the effect of Noggin on OCI/AML-3 cells we performed cell-cycle and apoptosis assays. Noggin significantly increased the percentage of cells in S/G2/M phase as early as 3h after treatment with a maximum effect by 24h (38% vs 27%). Noggin, also, decreased the percentage of cells undergoing apoptosis (2.8% vs 9.1%), an effect that became noticeable within 24h. Moreover, Noggin protected the leukemic cells against serum-deprivation and daunorubicin-induced apoptosis. As Noggin is a negative regulator of the BMP pathway we assessed the effect of Noggin on the expression of genes known to be affected by BMP, including DKK1, Wnt1, Wnt3a, Wnt5b, P21, P27, Bcl2, Bax, MSX1, MSX2, Id1, Id2, Id3, DLX1 and DLX2. While complete inhibition of SMAD 1,5,8 phosphorylation could be detected within 1 h of the addition of Noggin, gene expression changes were noticed beginning after 4h. Significant decreased expression at the RNA level was noted for DKK1, Wnt1, Wnt3a, Wnt5b, MSX1, Id1, Id3 and DLX2. Although substantial downregulation of the Wnt-pathway-related genes was seen, there was no change in this pathway overall activity as assessed by B-catenin protein and Wnt-pathway target-genes RNA levels. In summary, AML cells express and respond to the BMP inhibitor Noggin. BMP pathway inhibition increases the leukemic progenitors growth and self- renewal. The reduced expression of MSX1 is of interesting importance as MSX1 promotes p53 apoptotic function. The loss of MSX1 may thus reduce the cells sensitivity to apoptotic stimuli, such as daunorubicin.
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 ».