This review discusses current research on acute paediatric leukaemia, the leukaemic bone marrow (BM) microenvironment and recently discovered therapeutic opportunities to target leukaemia–niche interactions. The tumour microenvironment plays an integral role in conferring treatment resistance to leukaemia cells, this poses as a key clinical challenge that hinders management of this disease. Here we focus on the role of the cell adhesion molecule N-cadherin (CDH2) within the malignant BM microenvironment and associated signalling pathways that may bear promise as therapeutic targets. Additionally, we discuss microenvironment-driven treatment resistance and relapse, and elaborate the role of CDH2-mediated cancer cell protection from chemotherapy. Finally, we review emerging therapeutic approaches that directly target CDH2-mediated adhesive interactions between the BM cells and leukaemia cells.

Patient derived xenograft, PDX models are regarded as gold standard preclinical models in leukaemia research, especially in testing new drug combinations where typically 45 to 50 animals are used per assay. 9000 animal experiments are performed annually in leukaemia research with these expensive procedures being described as moderate severity, meaning they cause significant pain, suffering and visible distress to animals state. Furthermore, not all clinical leukaemia samples engraft and when they do data turnaround time can be between 6 to 12 months. Heavy dependence on animal models is because clinical leukaemia samples do not proliferate in vitro. Alternative cell line models though popular for drug testing are not biomimetic: they are not dependent on the microenvironment for survival, growth and treatment response and being derived from relapse samples they do not capture the molecular complexity observed at disease presentation. Here we have developed an in vitro platform to rapidly establish co cultures of patient derived leukaemia cells with 3D bone marrow mesenchyme spheroids, BM MSC spheroids. We optimise protocols for developing MSC spheroid leukaemia co-culture using clinical samples and deliver drug response data within a week. Using three patient samples representing distinct cytogenetics we show that patient derived leukaemia cells show enhanced proliferation when co-cultured with MSC spheroids. In addition, MSC spheroids provided improved protection against treatment. This makes our spheroids suitable to model treatment resistance, a major hurdle in current day cancer management. Given this 3Rs approach is 12 months faster in delivering clinical data, is a human cell based biomimetic model and 45 to 50 animals per drug response assay cheaper the anticipated target end users would include academia and pharmaceutical industry. This animal replacement prototype would facilitate clinically translatable research to be performed with greater ethical, social and financial sustainability.