The bone marrow immune microenvironment in CML: treatment responses, treatment-free remission, and therapeutic vulnerabilities

Patterson, S. D. and Copland, M. (2023) The bone marrow immune microenvironment in CML: treatment responses, treatment-free remission, and therapeutic vulnerabilities. Current Hematologic Malignancy Reports, 18(2), pp. 19-32. (doi: 10.1007/s11899-023-00688-6) (PMID:36780103) (PMCID:PMC9995533)

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Purpose of Review: Tyrosine kinase inhibitors (TKIs) are very successful for the treatment of chronic myeloid leukaemia (CML) but are not curative in most patients due to persistence of TKI-resistant leukaemia stem cells (LSCs). The bone marrow immune microenvironment (BME) provides protection to the LSC through multidimensional interactions, driving therapy resistance, and highlighting the need to circumvent these protective niches therapeutically. This review updates the evidence for interactions between CML cells and the immune microenvironment with a view to identifying targetable therapeutic vulnerabilities and describes what is known about the role of immune regulation in treatment-free remission (TFR). Recent Findings: 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. Summary: 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.

Item Type:Articles
Additional Information:SDP is funded by a Cancer Research UK Biomarker Award (CRCPJT\100006).
Glasgow Author(s) Enlighten ID:Patterson, Mr Shaun and Copland, Professor Mhairi
Authors: Patterson, S. D., and Copland, M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Current Hematologic Malignancy Reports
ISSN (Online):1558-822X
Published Online:13 February 2023
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in Current Hematologic Malignancy Reports 18(2): 19-32
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
309522Evaluation of key Biomarkers for the prediction of successful treatment-free remission (TFR) in chronic myeloid leukaemiaMhairi CoplandCancer Research UK (CRUK)CRCPJT\100006CS - Paul O'Gorman Leukaemia Research Centre