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| Status |
Public on Nov 11, 2024 |
| Title |
Paediatric Bone marrow Mesenchymal Stem cells support acute myeloid leukaemia cell survival and enhance chemoresistance via contact-independent mechanism |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Pediatric mesenchymal stem cells (pMSCs) within the bone marrow (BM) niche play a crucial role in regulating pediatric acute myeloid leukemia (pAML) survival and therapy resistance. In this study, we isolated pMSCs from pAML bone marrow samples and characterized their phenotype and differentiation potential. We performed coculture experiments with pAML cells in both autologous and allogenic settings, with and without direct contact. RNA-sequencing and multiplex immunoassays revealed that pMSCs promote pAML survival through changes in gene expression, cytokine secretion, and extracellular matrix (ECM) components, specifically enhancing chemoprotection from cytarabine and Gemtuzumab Ozogamicin (GO). Inhibition of the JAK/STAT and ERK pathways using ruxolitinib (RUX) abrogated the pMSC-induced chemoprotection, suggesting a contact-independent mechanism. These findings provide new insights into how the BM microenvironment contributes to therapy resistance in pediatric AML and highlights the potential for targeting pMSC-induced signaling pathways in treatment strategies.
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| Overall design |
Pediatric mesenchymal stem cells (pMSCs) were isolated from pediatric acute myeloid leukemia (pAML) bone marrow samples using the plastic adherence method. The pMSCs were characterized by surface markers (CD45-Lin-CD90+CD105+CD73+) and their ability to differentiate into adipocytes, osteoblasts, and chondrocytes. Coculture experiments were performed by directly co-culturing pAML cells with pMSCs, both with and without cytokine supplementation. Parallel experiments included a transwell system to assess contact-independent effects. RNA sequencing was conducted on pAML cells after coculture, and multiplex immunoassays were used to profile the secretome. Chemoprotection assays involved treatment with cytarabine (Ara-C) and Gemtuzumab Ozogamicin (GO), with apoptosis and cell cycle analyzed. Additionally, the role of JAK/STAT and ERK signaling was assessed using ruxolitinib (RUX) to inhibit these pathways and measure changes in chemoprotection.
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| Web link |
http:// https://doi.org/10.1111/bjh.19884
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| Contributor(s) |
Laing A, Elmarghany A, Alghaith A, Gouma A, Clarke C, Stevens T, Winton A, Cassells J, Harrison CJ, Schwab C, Gibson B, Keeshan K |
| Citation(s) |
- Laing A, Elmarghany A, Alghaith AA, Gouma A et al. Paediatric bone marrow mesenchymal stem cells support acute myeloid leukaemia cell survival and enhance chemoresistance via contact-independent mechanism. Br J Haematol 2025 Mar;206(3):858-863. PMID: 39523592
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| Submission date |
Sep 17, 2024 |
| Last update date |
Feb 17, 2025 |
| Contact name |
Alexander Winton |
| Organization name |
University Of Glasgow
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| Department |
School Of Cancer Science
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| Street address |
Wolfson Wohl Cancer Research Centre, Bearsden
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| City |
GLASGOW |
| ZIP/Postal code |
G61 1BD |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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