دورية أكاديمية
Hyperactive CREB subpopulations increase during therapy in pediatric B-lineage acute lymphoblastic leukemia
| العنوان: | Hyperactive CREB subpopulations increase during therapy in pediatric B-lineage acute lymphoblastic leukemia |
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| المؤلفون: | Dino Masic, Kayleigh Fee, Hayden Bell, Marian Case, Gabby Witherington, Sophie Lansbury, Juan Ojeda-Garcia, David McDonald, Claire Schwab, Frederik W. van Delft, Andrew Filby, Julie Anne Elizabeth Irving |
| المصدر: | Haematologica, Vol 108, Iss 4 (2022) |
| بيانات النشر: | Ferrata Storti Foundation, 2022. |
| سنة النشر: | 2022 |
| المجموعة: | LCC:Diseases of the blood and blood-forming organs |
| مصطلحات موضوعية: | Diseases of the blood and blood-forming organs, RC633-647.5 |
| الوصف: | Persistence of residual disease in acute lymphoblastic leukemia (ALL) during the initial stages of chemotherapy is associated with inferior survival. To better understand clonal evolution and mechanisms of chemoresistance, we used multiparameter mass cytometry, at single-cell resolution, to functionally characterize pediatric B-ALL cells at disease presentation and those persisting during induction therapy. Analysis of ALL cells from presentation samples (n=42) showed that the most abundant phosphosignals were pCREB, pH2AX and pHH3 and we identified JAK-STAT and RAS pathway activation in five of six patients with JAK or RAS genetic aberrations. The clonal composition of ALL was heterogeneous and dynamic during treatment but all viable cell clusters showed pCREB activation. Levels of pCREB in ALL cells were increased or maintained during therapy and high dimensional analysis revealed a subpopulation of ALL cells at presentation that was positive for pCREB/pHH3/pS6 which increased during treatment in some patients, implicating this signaling node in conferring a survival advantage to multi-agent induction therapy. The small molecule CREB inhibitor, 666-15, was shown to reduce CREB transcriptional activity and induce apoptosis in ALL patient-derived xenograft cells of varying cytogenetic subtypes in vitro, both in the presence and absence of stromal support. Together, these data suggest that the cAMP signaling pathway may provide an opportunity for minimal residual disease-directed therapy for many patients at high risk of relapse. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 0390-6078 1592-8721 |
| Relation: | https://haematologica.org/article/view/10877; https://doaj.org/toc/0390-6078; https://doaj.org/toc/1592-8721 |
| DOI: | 10.3324/haematol.2022.281177 |
| URL الوصول: | https://doaj.org/article/a0153007688e4868b6a8b5ad9310e368 |
| رقم الأكسشن: | edsdoj.0153007688e4868b6a8b5ad9310e368 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 03906078 15928721 |
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| DOI: | 10.3324/haematol.2022.281177 |