Bone Marrow Microenvironment Signalling and Chemoresistance in Acute Myeloid Leukemia

Abstract

Leukaemic blasts sheltering in the marrow niche survive chemotherapy that kills their circulating counterparts. The mechanism has been characterised in unusualdetail, the drugs to disrupt it exist and are licensed for other purposes, and after two decades the clinical  benefit remains unproven. Objectives: To review the published evidence on bone marrow microenvironment signalling as a mediator of chemoresistance in acute myeloid leukaemia: which interactions confer protection, how they have been demonstrated, which have been targeted clinically, and why the translation has been slower than the biology predicted. Material and Methods: Narrative review of mechanistic studies, preclinical models, early-phase trials and randomised evaluations indexed in PubMed and the major haematology journals. Studies were eligible if they characterised a marrow microenvironment interaction contributing to chemoresistance in acute
leukaemia, or reported clinical evaluation of an agent targeting one. No new patient data were generated and no patients were recruited; every estimate quoted is one published by the original investigators. Results: CXCR4 is overexpressed in 25 to 30 per cent of patients with acute myeloid leukaemia, and high expression is associated with poor prognosis. Its ligand CXCL12 is produced by marrow mesenchymal stromal cells and anchors blasts in contact with stroma and extracellular matrix, which generate growth-promoting and anti-apoptotic signals. Stromal co-culture confers chemoresistance in vitro and co-treatment with a CXCR4 antagonist restores chemosensitivity. In murine models, adding a CXCR4 antagonist to cytarabine reduced leukaemic burden and improved survival. Clinical translation has proceeded through a phase 1/2 chemosensitisation study in relapsed and refractory disease and, more recently, a randomised, double-blind, placebo-controlled phase 2 trial in which 128 patients in first remission received high-dose cytarabine with a selective CXCR4 antagonist or placebo. Conclusion: The mechanism is well established and reproducible across models, and the therapeutic principle remains largely untested at scale. Two decades after the interaction was described, the randomised evidence amounts to a single phase 2 trial of 128 patients. Abbreviations: AML – Acute Myeloid Leukaemia, ALL – Acute Lymphoblastic Leukaemia, BM – Bone Marrow, BMSC – Bone Marrow Stromal Cell, CXCR4 – CXC Chemokine Receptor 4, CXCL12 – CXC Motif Chemokine Ligand 12, SDF-1 – Stromal Cell-Derived Factor 1, VLA-4 – Very Late Antigen 4, VCAM-1 – Vascular Cell Adhesion Molecule 1, LSC – Leukaemic Stem Cell, MRD – Measurable Residual Disease, HSC – Haematopoietic Stem Cell, PDX – Patient-Derived Xenograft.