Recreating the Bone Marrow Microenvironment to Model Leukemic Stem Cell 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...
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doaj-f51574bff5c543ffbbd4778e5ec780462021-09-13T04:34:53ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-09-01910.3389/fcell.2021.662868662868Recreating the Bone Marrow Microenvironment to Model Leukemic Stem Cell QuiescenceEimear O’Reilly0Hojjat Alizadeh Zeinabad1Caoimhe Nolan2Jamileh Sefy3Thomas Williams4Marina Tarunina5Diana Hernandez6Yen Choo7Eva Szegezdi8Apoptosis Research Centre, Department of Biochemistry, School of Natural Sciences, National University of Ireland Galway, Galway, IrelandApoptosis Research Centre, Department of Biochemistry, School of Natural Sciences, National University of Ireland Galway, Galway, IrelandApoptosis Research Centre, Department of Biochemistry, School of Natural Sciences, National University of Ireland Galway, Galway, IrelandApoptosis Research Centre, Department of Biochemistry, School of Natural Sciences, National University of Ireland Galway, Galway, IrelandPlasticell Ltd., Stevenage Bioscience Catalyst, Stevenage, United KingdomPlasticell Ltd., Stevenage Bioscience Catalyst, Stevenage, United KingdomPlasticell Ltd., Stevenage Bioscience Catalyst, Stevenage, United KingdomPlasticell Ltd., Stevenage Bioscience Catalyst, Stevenage, United KingdomApoptosis Research Centre, Department of Biochemistry, School of Natural Sciences, National University of Ireland Galway, Galway, IrelandThe 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 G0 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.https://www.frontiersin.org/articles/10.3389/fcell.2021.662868/fullleukemic stem cellacute myeloid leukemiabone marrow microenvironmentquiescencethree-dimensional model |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Eimear O’Reilly Hojjat Alizadeh Zeinabad Caoimhe Nolan Jamileh Sefy Thomas Williams Marina Tarunina Diana Hernandez Yen Choo Eva Szegezdi |
spellingShingle |
Eimear O’Reilly Hojjat Alizadeh Zeinabad Caoimhe Nolan Jamileh Sefy Thomas Williams Marina Tarunina Diana Hernandez Yen Choo Eva Szegezdi Recreating the Bone Marrow Microenvironment to Model Leukemic Stem Cell Quiescence Frontiers in Cell and Developmental Biology leukemic stem cell acute myeloid leukemia bone marrow microenvironment quiescence three-dimensional model |
author_facet |
Eimear O’Reilly Hojjat Alizadeh Zeinabad Caoimhe Nolan Jamileh Sefy Thomas Williams Marina Tarunina Diana Hernandez Yen Choo Eva Szegezdi |
author_sort |
Eimear O’Reilly |
title |
Recreating the Bone Marrow Microenvironment to Model Leukemic Stem Cell Quiescence |
title_short |
Recreating the Bone Marrow Microenvironment to Model Leukemic Stem Cell Quiescence |
title_full |
Recreating the Bone Marrow Microenvironment to Model Leukemic Stem Cell Quiescence |
title_fullStr |
Recreating the Bone Marrow Microenvironment to Model Leukemic Stem Cell Quiescence |
title_full_unstemmed |
Recreating the Bone Marrow Microenvironment to Model Leukemic Stem Cell Quiescence |
title_sort |
recreating the bone marrow microenvironment to model leukemic stem cell quiescence |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cell and Developmental Biology |
issn |
2296-634X |
publishDate |
2021-09-01 |
description |
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 G0 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. |
topic |
leukemic stem cell acute myeloid leukemia bone marrow microenvironment quiescence three-dimensional model |
url |
https://www.frontiersin.org/articles/10.3389/fcell.2021.662868/full |
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