A Novel In Vitro Model of the Bone Marrow Microenvironment in Acute Myeloid Leukemia Identifies CD44 and Focal Adhesion Kinase as Therapeutic Targets to Reverse Cell Adhesion-Mediated Drug Resistance

Targeted inhibition of non-canonical NF-kB subunits

Summary

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.

Publication
Cancers. 2025 Jan 3;17(1):135.
Kim Sharp
Kim Sharp
Former PhD student

PhD student working on targeting leukaemic stem cells in Acute Myeloid Leukaemia using ProTide nucleoside analogues.

Lauren Stott
Lauren Stott
PhD student
Emma Kennedy
Emma Kennedy
Postdoctoral Researcher

Postdoctoral researcher interested in Chronic Lymphocytic Leukaemia, Cell Signalling, Molecular Basis of Disease and Personalised Medicine.

Iona Ashworth
Iona Ashworth
PhD Clinical Fellow