| Autor: |
Yoana Arroyo-Berdugo, Maria Sendino, David Greaves, Natalia Nojszewska, Orest Idilli, Chi Wai So, Lucy Di Silvio, Ruby Quartey-Papafio, Farzin Farzaneh, Jose Antonio Rodriguez, Yolanda Calle |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Cancers; Volume 15; Issue 7; Pages: 1988 |
| Popis: |
The interactions between Acute Myeloid Leukaemia (AML) leukemic stem cells and the bone marrow (BM) microenvironment play a critical role during AML progression and resistance to drug treatments. Therefore, the identification of novel therapies requires drug-screening methods using in vitro co-culture models that closely recreate the cytoprotective BM setting. We have developed a new fluorescence-based in vitro co-culture system scalable to high throughput for measuring the concomitant effect of drugs on AML cells and the cytoprotective BM microenvironment. eGFP-expressing AML cells are co-cultured in direct contact with mCherry-expressing BM stromal cells for the accurate assessment of proliferation, viability, and signaling in both cell types. This model identified several efficacious compounds that overcome BM stroma-mediated drug resistance against daunorubicin, including the chromosome region maintenance 1 (CRM1/XPO1) inhibitor KPT-330. In silico analysis of genes co-expressed with CRM1, combined with in vitro experiments using our new methodology, also indicates that the combination of KPT-330 with the AURKA pharmacological inhibitor alisertib circumvents the cytoprotection of AML cells mediated by the BM stroma. This new experimental model and analysis provide a more precise screening method for developing improved therapeutics targeting AML cells within the cytoprotective BM microenvironment. This research received funding from Cancer Research UK (reference C34579/A20784) and the Basque Country Government (reference IT1547-22). |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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