A Novel AHI-1-BCR-ABL-JAK2 Interaction Complex Mediates Cellular Resistance to Tyrosine Kinase Inhibitors in CML .
Notice bibliographique
Résumé
Abstract Abstract 38 The molecular signature of chronic myeloid leukemia (CML) is the BCR-ABL fusion gene originating in a multipotent hematopoietic stem cell. The BCR-ABL oncoprotein (p210BCR-ABL) has constitutively elevated tyrosine kinase activity that perturbs several signalling cascades, including the PI3K/AKT, JAK2/STAT5, NF-kB, and RAS/MAPK pathways. The current first line treatment for CML is the tyrosine kinase inhibitor imatinib mesylate (IM) that induces clinical remission in most chronic phase CML patients. However, early relapses and IM-resistant disease have emerged and are frequently associated with mutations in the BCR-ABL kinase domain. Our recent studies indicate that CML stem cells are less responsive to IM and other tyrosine kinase inhibitors and are critical target population for IM resistance. It is therefore critical to identify other therapies that target CML stem cells to prevent acquisition of resistance. One candidate target is AHI-1 (Abelson helper integration site 1), a recently discovered oncogene that is deregulated in primary leukemic stem cells from CML patients. AHI-1 contains several domains indicative of signalling functions, including an SH3 and a WD40-repeat domain. We have recently identified a novel AHI-1-BCR-ABL-JAK2 interaction complex that modulates BCR-ABL transforming activity both in vitro and in vivo and play a key role in the IM response/resistance of primary CML stem/progenitor cells. To investigate AHI-1's involvement in mediating this cellular resistance to IM and to test the comparative ability of new ABL and JAK2 inhibitors to inhibit this complex in CML cells, AHI-1 was either stably overexpressed in K562 cells by transduction of EF1a-AHI-1-IRES-YFP lentivirus or suppressed in K562 cells using RNA interference. Interestingly, an increase in cellular proliferation and colony formation and a decrease in apoptosis were observed in the presence of 1, 5 and 10 uM of IM when AHI-1 was overexpressed. Survival of these cells was similar to IM resistant K562 cells, which are highly resistant to IM in vitro and display higher AHI-1 protein expression than parental K562 cells. Suppression of AHI-1 had the opposite effect, with cells displaying heightened sensitivity to IM at concentrations as low as 1 uM. Phosphorylation and total protein expression levels of several proteins known to be involved in BCR-ABL signalling, including JAK2, STAT5, MAPK, SRC, AKT and NF-kB (P105, P50, and P65 subunits), were quantified by Western blot analysis. Elevated phosphorylation and total protein expression levels of several of these proteins were observed when AHI-1 was overexpresessed, in particular in the JAK2/STAT5 pathway and especially in the presence of Interleukin 3. Due to the strong effects AHI-1 had on this signalling cascade, we next inhibited JAK2 activity using a selective JAK2 inhibitor, TG101209, that is highly effective against the V617F mutation and inhibits JAK2 and STAT5 activities in polycythemia vera progenitor cells. AHI-1 overexpressing cells showed reduced proliferation and colony formation when treated with IM and TG101209 in combination compared to either IM or TG101209 alone. Interestingly, treatment with IM (5 uM) or dasatinib (150 nM, DA) in combination with TG101209 (100 nM) resulted in greater inhibition (81% and 85%) of CD34+ CML stem/progenitor cells from IM nonresponders (n=4), compared to the same cells treated with a combination of IM and DA (∼60%, p<0.05), as measured by colony-forming cell assays. CFSE tracking analysis of cell division in these cells further demonstrated additive antiproliferative activity as a result of combined ABL and JAK2 inhibitors. These results suggest that targeting both BCR-ABL and JAK2 activities may be a potential therapeutic option for IM resistant patients. 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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».