期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 13, 页码 -出版社
MDPI
DOI: 10.3390/ijms22136888
关键词
bone marrow microenvironment; leukaemia; mesenchymal stem cell; endothelial cell; osteoclast; osteoblast; therapeutic agents
资金
- Children's Leukaemia and Cancer Research Foundation (CLCRF) Perth, Western Australia [1184963]
- Cancer Australia, Cure Cancer
- Leukaemia Foundation of Australia
- National Health and Medical Research Council of Australia (NHMRC) [APP1142627]
Uniform prospective clinical trials have improved remission rates and survival for patients with acute myeloid leukaemia and acute lymphoblastic leukaemia in recent decades. However, high-risk patients continue to have inferior outcomes due to mechanisms where leukaemic cells hijack the bone marrow microenvironment. Targeting the cellular interactions within the leukaemia-bone marrow niche is an exciting novel strategy with significant potential to enhance treatment efficacy and improve patient outcomes.
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.
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