Therapeutic Targeting of the Leukaemia Microenvironment
In recent decades, the conduct of uniform prospective clinical trials has led to improved remission rates and survival for patients with acute myeloid leukaemia and acute lymphoblastic leukaemia. However, high-risk patients continue to have inferior outcomes, where chemoresistance and relapse are co...
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doaj-2f381b554db34e9fb0b1908a71f5ce452021-07-15T15:37:13ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-06-01226888688810.3390/ijms22136888Therapeutic Targeting of the Leukaemia MicroenvironmentVincent Kuek0Anastasia M. Hughes1Rishi S. Kotecha2Laurence C. Cheung3Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, AustraliaLeukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, AustraliaLeukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, AustraliaLeukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, AustraliaIn recent decades, the conduct of uniform prospective clinical trials has led to improved remission rates and survival for patients with acute myeloid leukaemia and acute lymphoblastic leukaemia. However, high-risk patients continue to have inferior outcomes, where chemoresistance and relapse are common due to the survival mechanisms utilised by leukaemic cells. One such mechanism is through hijacking of the bone marrow microenvironment, where healthy haematopoietic machinery is transformed or remodelled into a hiding ground or “sanctuary” where leukaemic cells can escape chemotherapy-induced cytotoxicity. The bone marrow microenvironment, which consists of endosteal and vascular niches, can support leukaemogenesis through intercellular “crosstalk” with niche cells, including mesenchymal stem cells, endothelial cells, osteoblasts, and osteoclasts. Here, we summarise the regulatory mechanisms associated with leukaemia–bone marrow niche interaction and provide a comprehensive review of the key therapeutics that target CXCL12/CXCR4, Notch, Wnt/b-catenin, and hypoxia-related signalling pathways within the leukaemic niches and agents involved in remodelling of niche bone and vasculature. From a therapeutic perspective, targeting these cellular interactions is an exciting novel strategy for enhancing treatment efficacy, and further clinical application has significant potential to improve the outcome of patients with leukaemia.https://www.mdpi.com/1422-0067/22/13/6888bone marrow microenvironmentleukaemiamesenchymal stem cellendothelial cellosteoclastosteoblast |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Vincent Kuek Anastasia M. Hughes Rishi S. Kotecha Laurence C. Cheung |
spellingShingle |
Vincent Kuek Anastasia M. Hughes Rishi S. Kotecha Laurence C. Cheung Therapeutic Targeting of the Leukaemia Microenvironment International Journal of Molecular Sciences bone marrow microenvironment leukaemia mesenchymal stem cell endothelial cell osteoclast osteoblast |
author_facet |
Vincent Kuek Anastasia M. Hughes Rishi S. Kotecha Laurence C. Cheung |
author_sort |
Vincent Kuek |
title |
Therapeutic Targeting of the Leukaemia Microenvironment |
title_short |
Therapeutic Targeting of the Leukaemia Microenvironment |
title_full |
Therapeutic Targeting of the Leukaemia Microenvironment |
title_fullStr |
Therapeutic Targeting of the Leukaemia Microenvironment |
title_full_unstemmed |
Therapeutic Targeting of the Leukaemia Microenvironment |
title_sort |
therapeutic targeting of the leukaemia microenvironment |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-06-01 |
description |
In recent decades, the conduct of uniform prospective clinical trials has led to improved remission rates and survival for patients with acute myeloid leukaemia and acute lymphoblastic leukaemia. However, high-risk patients continue to have inferior outcomes, where chemoresistance and relapse are common due to the survival mechanisms utilised by leukaemic cells. One such mechanism is through hijacking of the bone marrow microenvironment, where healthy haematopoietic machinery is transformed or remodelled into a hiding ground or “sanctuary” where leukaemic cells can escape chemotherapy-induced cytotoxicity. The bone marrow microenvironment, which consists of endosteal and vascular niches, can support leukaemogenesis through intercellular “crosstalk” with niche cells, including mesenchymal stem cells, endothelial cells, osteoblasts, and osteoclasts. Here, we summarise the regulatory mechanisms associated with leukaemia–bone marrow niche interaction and provide a comprehensive review of the key therapeutics that target CXCL12/CXCR4, Notch, Wnt/b-catenin, and hypoxia-related signalling pathways within the leukaemic niches and agents involved in remodelling of niche bone and vasculature. From a therapeutic perspective, targeting these cellular interactions is an exciting novel strategy for enhancing treatment efficacy, and further clinical application has significant potential to improve the outcome of patients with leukaemia. |
topic |
bone marrow microenvironment leukaemia mesenchymal stem cell endothelial cell osteoclast osteoblast |
url |
https://www.mdpi.com/1422-0067/22/13/6888 |
work_keys_str_mv |
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