Adhesion of leukaemic cells in the bone marrow microenvironment (BMME), play an important role in the resistance of AML to current therapeutic agents. Although, therapies that disrupt AML cell adherence in the BMME, and release them into the less protective peripheral circulation, have been trialled (e.g. Plerixafor targeting CXCR4), their success has been limited. Here we report efforts to create a multi-cellular, physiologically relevant, in-vitro model of the adhesive and chemo-protective AML BMME. Firstly, we demonstrated that this model recapitulates the cell adhesion-mediated drug resistance (CAM-DR) seen clinically. Secondly, we used it to explore the altered transcriptional programme induced by cell adhesion and subsequently as a drug testing platform to rationally target and disrupt this cellular process to reverse the protective effects of the AML BMME. The key finding was that dual targeting of CD44 and FAK (using anti-CD44 and the clinical grade FAK inhibitor defactinib) synergistically inhibit adhesion of the most primitive CD34high AML cells that are associated with CAM-DR and relapse.