Investigating the role of the bone marrow microenvironment in the pathogenesis, treatment resistance and relapse of acute myeloid leukaemia following chemotherapy and after bone marrow transplantation
Acute myeloid leukaemia / Posted 1 year ago
Relapse (the chance of disease coming back after treatment) is very high in acute myeloid leukaemia even after curative approaches with intensive chemotherapy and bone marrow transplantation. The bone marrow microenvironment which includes the stromal cells (MSC) surrounding the blood cells/leukaemia cells is thought to be a key player in chemotherapy resistance and acts as a sanctuary site for minimal residual disease (MRD) from which relapse may occur. Once MRD is detectable, frank relapse is likely within a short time-frame affording insufficient time for effective salvage interventions. In addition, a large proportion of patients there is no informative MRD marker thus disease relapse can occur with little warning. In this study, we aim to investigate the role of patient MSC in protecting AML cells at different stages of treatment including post chemotherapy and after stem cell transplantation. By developing a 3D dynamic model of leukaemia-stroma interactions which can better mimic the dynamics of cell interactions occurring in the patient, we aim to identify critical determinants of stromal protection that may help in the design of new compounds and strategies that can overcome minimal residual disease and improve clinical outcomes. The project will directly compare the functional ability of AML derived MSC from patients to normal MSC from healthy donors to examine changes in patient MSC that may herald relapse prior to the detection of MRD. It will involve the study of the adhesive properties and homing abilities of AML cells, cytokine secretion by MSC and mechanistic pathway analyses. We will use molecular and pharmacological inhibition of novel targets to model therapeutic interventions that prime the niche in favour of normal cells. These targets will be validated through screening an expanded cohort of patient samples and correlating poor niche biomarkers with clinical outcomes.