The role of patient bone marrow microenvironment in relapsing acute myeloid leukaemia after stem cell transplantation: a study to pre-empt early relapse
Up to 40% of leukaemia patients receiving a bone marrow transplant (BMT) from a donor will suffer disease recurrence/relapse within a year, significantly shortening their overall survival.
Once leukaemia cells are detectable in the patient's bone marrow (BM), it is extremely difficult to control the disease as the rapid growth rate of acute leukaemia (AML) coupled with resistance to drug treatment severely reduces the number of patients who can be helped at this stage.
This places a considerable burden upon the healthcare services in Wales as these patients often require urgent treatment and intensive care. The mechanisms underlying relapse following donor grafts are poorly understood. An early warning system to identify patients destined to relapse following BMT is urgently needed before leukaemia cells are detectable in their BM.
Current research suggests that the microenvironment of the bone marrow niche into which the transplanted normal donor stem cells migrate may be unable to support normal cell growth and have a significant impact on the re-emergence of the patient's leukaemia.
Work within our group has focused on the isolation and culture of patient microenvironment cells. These stromal cells line the bone marrow niche and provide a three-dimensional structure with which blood cells interact to survive and grow.
Drug development to date has focused on clearing the bulk of leukaemic cells and how to target the 'Leukaemic stem cell', which may give rise to relapse. However little work has been undertaken to discover the mechanisms by which the bone marrow microenvironment and the supporting stromal cells communicate and preferentially support leukaemic cells.
We aim to develop a novel dynamic microfluidic 3D microenvironment model of post-BMT AML using patient samples (for which ethical approval is in place), which more closely represents the clinical setting than our current in vitro models. We will identify associated molecular and phenotypic changes in the supporting cells of the patient bone marrow microenvironment (MSC) that influence the ability to support the growth of normal donor cells. This system will be used to explore direct and indirect methods of AML:
MSC communication through pharmaceutical and molecular modification of adhesion and microvesicle interactions of the MSC stroma. These interactions will be monitored through live cell imaging which allows the interrogation of cell communication in situ under physiologically relevant conditions in this optically inert system.
Application of the model will include investigating microenvironmental priming of patient MSCs using current and novel therapeutic interventions and validation of the platform using molecular profiling to identify biomarkers of change which correlate with clinical outcomes.
By identifying this critical time window post-transplant when the patient's BM signals a failing ability to support normal donor blood cells and the mechanisms underpinning this process will enable development of a blood detectable biomarker that is predictive of patients at high risk of relapse.
This will provide a critical window to enable early direct clinical intervention with current and novel treatments which has the potential to save a significant number of patient lives, impact on clinical governance and change the way all patients are monitored following a bone marrow transplant.