Therapeutic Targeting of the Leukaemia Microenvironment

Abstract

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.

Characterization of mesenchymal stem cells in pre-B acute lymphoblastic leukemia

“…In summary, significant progress has been made over recent years in the development of therapies which target the B-ALL microenvironment (Kuek et al, 2021). However, the BMM of certain high-risk B-ALL subtypes, such as BCR-ABL1, remain under investigated.…”

Olive leaves extract alleviates inflammation and modifies the intrinsic apoptotic signal in the leukemic bone marrow

“…Leukemia occurs in individuals of all age groups. Relapse in critical patients and resistance to chemotherapy cause severe hematological complications and therapeutic incompatibility specifically after a chemotherapy eventuating in death of the leukemia patients ( 1 ). The leukemic cells and other cells in the BM microenvironment secrete several soluble factors in a dysregulated manner, altering cell signalling and aiding the leukemic cells’ survival and resistance to chemotherapy.…”

Shotgun Proteomics of Co-Cultured Leukemic and Bone Marrow Stromal Cells from Different Species as a Preliminary Approach to Detect Intercellular Protein Transfer

“…Moreover, the transfer of membrane-enclosed vesicles from MSC to chronic myeloid leukemia cells protects the latter against imatinib [ 9 ], and the mitochondrial transfer from MSC to ALL or AML cells, protects against cytarabine [ 11 , 15 ]. Disruption of the cellular interactions between leukemic cells and the BM is considered a promising therapeutic option [ 7 , 16 , 17 , 18 ]. One of the experimental models to study these interactions is the culture of leukemic cells growing around stromal spheroids (3D co-culture), which mimics the hypoxic conditions, the presence of different niches, and the transition between leukemic cells with stem cell features and proliferating blasts [ 19 , 20 , 21 ].…”