Does sphingosine kinase 1 contribute towards bone marrow mediated chemotherapy resistance in Acute Myeloid Leukaemia?

Cancer drug resistance (chemoresistance) is a major contributing factor towards poor survival in Acute Myeloid Leukaemia (AML); the second most common leukaemia in adults and children. Cross-talk between AML cells, and bone marrow (BM) dwelling cells, significantly contributes towards chemoresistance. Cancer-supporting macrophages (immune cells) and fibroblasts (supportive cells) are elevated in the BM of AML patients, but their role in chemoresistance has not been fully elucidated. Our initial findings from our collaborative studies suggest that cancer-supporting macrophages are increased in the BM of AML patients compared to healthy individuals. Both direct culture of leukaemic cells together with macrophages and fibroblasts as well as substances released from these cells, can protect AML cells from cancer drugs. We predict that macrophages and fibroblasts protect AML cells through the induction of the sphingosine kinase 1 (SK1) cell survival pathway. To interrogate this, we will utilize 3D co-culture systems, more accurately reflecting conditions within the BM microenvironment, and target the SK1 pathway to determine if we can reverse the chemoprotective effects of macrophages and fibroblasts on AML cells. This study will uncover novel targetable chemoresistance mechanisms driving the development of much needed new drugs to safely and effectively treat, and improve AML patient survival.