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 3 years 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.

  • Inclusion Criteria : Adult patients with acute myeloid leukaemia undergoing treatment at the University Hospital of Wales, Department of Haematology who are able to provide informed consent. All prospective bone marrow donors must satisfy the requirements for bone marrow donation as set out by the Welsh Bone Marrow Donor Registry. These requirements include satisfactory medical screening and consent for the donation process as a whole.
  • Exclusion Criteria : Non-AML patients Lack of informed consent or lack of capacity to consent. Any Bone Marrow donors unwilling to give consent for the use of their bone marrow in the research study.
  • Study start date : 01/11/2017
  • Study end date : 01/11/2022
  • Wales-Based Study Contact : please speak to your clinican
  • Principal Investigator : Dr Caroline Alvares
Contact details

Cardiff University,Cardiff

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