Journal
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
Volume 9, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2021.662868
Keywords
leukemic stem cell; acute myeloid leukemia; bone marrow microenvironment; quiescence; three-dimensional model
Categories
Funding
- European Union's Horizon 2020 Research and Innovation Program DISCOVER [777995]
- Science Foundation Ireland [SFI/TIDA/B2388]
- Irish Cancer Society [BCNI/ICS/B3042]
- Irish Research Council [EPSG/2015/91]
- NUI Galway
- College of Science Scholarships and Thomas Crawford Hayes fund, NUI Galway
- Marie Curie Actions (MSCA) [777995] Funding Source: Marie Curie Actions (MSCA)
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The main challenge in AML treatment is relapse, driven by quiescent LSCs in the BMM. Culturing AML cells in a 3D system can replicate the quiescence-driving BMM, providing a platform for high-throughput screening of combination drug treatments to break BMM-mediated LSC quiescence.
The main challenge in the treatment of acute myeloid leukemia (AML) is relapse, as it has no good treatment options and 90% of relapsed patients die as a result. It is now well accepted that relapse is due to a persisting subset of AML cells known as leukemia-initiating cells or leukemic stem cells (LSCs). Hematopoietic stem cells (HSCs) reside in the bone marrow microenvironment (BMM), a specialized niche that coordinates HSC self-renewal, proliferation, and differentiation. HSCs are divided into two types: long-term HSCs (LT-HSCs) and short-term HSCs, where LT-HSCs are typically quiescent and act as a reserve of HSCs. Like LT-HSCs, a quiescent population of LSCs also exist. Like LT-HSCs, quiescent LSCs have low metabolic activity and receive pro-survival signals from the BMM, making them resistant to drugs, and upon discontinuation of therapy, they can become activated and re-establish the disease. Several studies have shown that the activation of quiescent LSCs may sensitize them to cytotoxic drugs. However, it is very difficult to experimentally model the quiescence-inducing BMM. Here we report that culturing AML cells with bone marrow stromal cells, transforming growth factor beta-1 and hypoxia in a three-dimensional system can replicate the quiescence-driving BMM. A quiescent-like state of the AML cells was confirmed by reduced cell proliferation, increased percentage of cells in the G(0) cell cycle phase and a decrease in absolute cell numbers, expression of markers of quiescence, and reduced metabolic activity. Furthermore, the culture could be established as co-axial microbeads, enabling high-throughput screening, which has been used to identify combination drug treatments that could break BMM-mediated LSC quiescence, enabling the eradication of quiescent LSCs.
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