Role of CXCR4 in the progression and therapy of acute leukaemia

Abstract

Chemokines are small peptides with molecular weights of 8-12 KDa, which are secreted by multiple types of cells, such as immune cells, stromal cells and tumour cells. Chemokine receptors are seven-transmembrane G-protein-coupled receptors (GPCRs), and one receptor can bind to multiple chemokines. 1,2 Conversely, one chemokine can recognize several receptors. 1,2 CXCR4 was first discovered as a cofactor facilitating the entry of human immunodeficiency virus (HIV) into CD4 + T cells and was then classified into GPCR subfamily. 3,4 CXCR4 is widely expressed in many types of cells, including haematopoietic stem cells (HSCs), T lymphocytes, B lymphocytes, monocytes, macrophages, epithelial cells, endothelial cells and neurons. 5 Stromal-derived factor 1 (SDF-1), also known as CXCL12, is the only ligand for CXCR4 but can also bind to CXCR7.After the engagement of SDF-1 and CXCR4, many intracellular pathways are activated, including RAS-MAPK, PI3K-AKT-mTOR and JAK-STAT, which then regulate chemotaxis, gene expression and cell survival. 6,7 Sdf1 or Cxcr4 homozygous mutations in mice resulted in embryonic lethality, and the development of B lymphocytes and myeloid cells was severely impaired. 8,9 Other defects, including cardiac ventricular septal defect and defective formation of large vessels supplying the gastrointestinal tracts, were found. 10 HSCs express high levels of CXCR4 and can migrate from the foetal

Recent Advances in CXCL12/CXCR4 Antagonists and Nano-Based Drug Delivery Systems for Cancer Therapy

“…In the TME, high expression levels of CXCR4 increase the infiltration of myeloid-derived suppressor cells (MDSCs) but reduces CD8+ T cell infiltration, thus inhibiting the immune response [ 40 ]. CXCR4 also increases Treg infiltration in tumors and releases an immunosuppressor of T cells by suppressing IFN-γ production, promoting proliferation, and inhibiting apoptosis [ 41 ].…”

Fibroblast Common Serum Response Signature-Related Classification Affects the Tumour Microenvironment and Predicts Prognosis in Bladder Cancer

“…To the best of our knowledge, few studies have evaluated the role of SERPINB7 , CRISPLD2 , EML1 , and TRPC4 in BLCA. As one of the most widely studied chemokines, CXCL12 has been reported in both haematological and solid tumours, including acute myeloid leukaemia [ 20 ], lymphoma [ 21 ], cervical cancer [ 22 ], lung cancer [ 23 ], colorectal cancer [ 24 ], and breast cancer [ 25 ]. It is mainly involved in the formation of tumour blood vessels, tumour growth, and metastasis.…”

Targeting Leukemia-Initiating Cells and Leukemic Niches: The Next Therapy Station for T-Cell Acute Lymphoblastic Leukemia?

“…CXCL12 (also termed stromal cell derived factor-1, SDF-1) is a chemotactic factor, and its receptor CXCR4 is a highly conserved G-protein-coupled seven transmembrane receptor. Since stromal-vascular BM niches secrete abundant CXCL12, whereas CXCR4 is primarily expressed on HSCs and malignant cells, the CXCL12/CXCR4 axis becomes a key pathway for both normal hematopoiesis and cancer cell homing to the BM [ 62 , 63 , 64 , 65 ]. Indeed, T-ALL cells express high surface levels of CXCR4 in a calcineurin-dependent manner, and CXCR4 silencing impairs migration and survival of leukemic cells, as well as T-LIC activity [ 66 ].…”