The Bone Marrow Immune Microenvironment in CML: Treatment Responses, Treatment-Free Remission, and Therapeutic Vulnerabilities.

Intracellular signalling downstream of the chemotactic CXCL12-CXCR4 axis, responsible for disrupted homing in CML, has been elucidated in LSCs, highlighting novel therapeutic opportunities. In addition, LSCs expressing CXCL12-cleaving surface protein CD26 were highly correlated with CML burden, building on existing evidence. Newer findings implicate the adhesion molecule CD44 in TKI resistance, while JAK/STAT-mediated resistance to TKIs may occur downstream of extrinsic signalling in the BME. Exosomal BME-LSC cross-communication has also been explored. Finally, further detail on the phenotypes of natural killer (NK) cells putatively involved in maintaining successful TFR has been published, and NK-based immunotherapies are discussed. Recent studies highlight and build on our understanding of the BME in CML persistence and TKI resistance, pinpointing therapeutically vulnerable interactions. Repurposing existing drugs and/or the development of novel inhibitors targeting these relationships may help to overcome these issues in TKI-resistant CML and be used as adjuvant therapy for sustained TFR.