Article ; Online: Dissecting the role of the CXCL12/CXCR4 axis in acute myeloid leukaemia.
British journal of haematology
2020 Volume 189, Issue 5, Page(s) 815–825
Abstract: Acute myeloid leukaemia (AML) is the most common adult acute leukaemia with the lowest survival rate. It is characterised by a build-up of immature myeloid cells anchored in the protective niche of the bone marrow (BM) microenvironment. The CXCL12/CXCR4 ... ...
Abstract | Acute myeloid leukaemia (AML) is the most common adult acute leukaemia with the lowest survival rate. It is characterised by a build-up of immature myeloid cells anchored in the protective niche of the bone marrow (BM) microenvironment. The CXCL12/CXCR4 axis is central to the pathogenesis of AML as it has fundamental control over AML cell adhesion into the protective BM niche, adaptation to the hypoxic environment, cellular migration and survival. High levels of CXCR4 expression are associated with poor relapse-free and overall survival. The CXCR4 ligand, CXCL12 (SDF-1), is expressed by multiple cells types in the BM, facilitating the adhesion and survival of the malignant clone. Blocking the CXCL12/CXCR4 axis is an attractive therapeutic strategy providing a 'multi-hit' therapy that both prevents essential survival signals and releases the AML cells from the BM into the circulation. Once out of the protective niche of the BM they would be more susceptible to destruction by conventional chemotherapeutic drugs. In this review, we disentangle the diverse roles of the CXCL12/CXCR4 axis in AML. We then describe multiple CXCR4 inhibitors, including small molecules, peptides, or monoclonal antibodies, which have been developed to date and their progress in pre-clinical and clinical trials. Finally, the review leads us to the conclusion that there is a need for further investigation into the development of a 'multi-hit' therapy that targets several signalling pathways related to AML cell adhesion and maintenance in the BM. |
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MeSH term(s) | Animals ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antineoplastic Agents/blood ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Bone Marrow/pathology ; Cell Adhesion/drug effects ; Cell Adhesion/physiology ; Cell Hypoxia ; Cell Movement/physiology ; Cell-Derived Microparticles ; Chemokine CXCL12/physiology ; Clinical Trials as Topic ; Drug Evaluation, Preclinical ; Drug Resistance, Neoplasm ; Gene Expression Regulation, Leukemic/drug effects ; Gene Expression Regulation, Leukemic/physiology ; Heterocyclic Compounds/pharmacology ; Heterocyclic Compounds/therapeutic use ; Humans ; Leukemia, Myeloid, Acute/blood ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/metabolism ; Leukemia, Myeloid, Acute/pathology ; Mice ; Molecular Targeted Therapy ; Neoplasm Proteins/antagonists & inhibitors ; Neoplasm Proteins/physiology ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Peptides/therapeutic use ; Peptides, Cyclic/therapeutic use ; Pyridines/therapeutic use ; Receptors, CXCR4/antagonists & inhibitors ; Receptors, CXCR4/physiology ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Stem Cell Niche ; Stromal Cells/metabolism ; Stromal Cells/pathology ; Tumor Microenvironment | |||||
Chemical Substances | 4-fluorobenzoyl-TN-14003 ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; CXCL12 protein, human ; CXCR4 protein, human ; CXCR4 protein, mouse ; Chemokine CXCL12 ; Heterocyclic Compounds ; LY2510924 ; N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine ; Neoplasm Proteins ; Peptides ; Peptides, Cyclic ; Pyridines ; Receptors, CXCR4 ; ulocuplumab (7KNP87L4X4) ; plerixafor (S915P5499N) | |||||
Language | English | |||||
Publishing date | 2020-03-05 | |||||
Publishing country | England | |||||
Document type | Journal Article ; Research Support, Non-U.S. Gov't ; Review | |||||
ZDB-ID | 80077-6 | |||||
ISSN | 1365-2141 ; 0007-1048 | |||||
ISSN (online) | 1365-2141 | |||||
ISSN | 0007-1048 | |||||
DOI | 10.1111/bjh.16456 | |||||
Shelf mark |
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Database | MEDical Literature Analysis and Retrieval System OnLINE |
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