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

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 th...

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Autores principales: Patterson, Shaun David, Copland, Mhairi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9995533/
https://www.ncbi.nlm.nih.gov/pubmed/36780103
http://dx.doi.org/10.1007/s11899-023-00688-6
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author Patterson, Shaun David
Copland, Mhairi
author_facet Patterson, Shaun David
Copland, Mhairi
author_sort Patterson, Shaun David
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description 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.
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spelling pubmed-99955332023-03-10 The Bone Marrow Immune Microenvironment in CML: Treatment Responses, Treatment-Free Remission, and Therapeutic Vulnerabilities Patterson, Shaun David Copland, Mhairi Curr Hematol Malig Rep Chronic Myeloid Leukemias (V Oehler, Section Editor) 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. Springer US 2023-02-13 2023 /pmc/articles/PMC9995533/ /pubmed/36780103 http://dx.doi.org/10.1007/s11899-023-00688-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Chronic Myeloid Leukemias (V Oehler, Section Editor)
Patterson, Shaun David
Copland, Mhairi
The Bone Marrow Immune Microenvironment in CML: Treatment Responses, Treatment-Free Remission, and Therapeutic Vulnerabilities
title The Bone Marrow Immune Microenvironment in CML: Treatment Responses, Treatment-Free Remission, and Therapeutic Vulnerabilities
title_full The Bone Marrow Immune Microenvironment in CML: Treatment Responses, Treatment-Free Remission, and Therapeutic Vulnerabilities
title_fullStr The Bone Marrow Immune Microenvironment in CML: Treatment Responses, Treatment-Free Remission, and Therapeutic Vulnerabilities
title_full_unstemmed The Bone Marrow Immune Microenvironment in CML: Treatment Responses, Treatment-Free Remission, and Therapeutic Vulnerabilities
title_short The Bone Marrow Immune Microenvironment in CML: Treatment Responses, Treatment-Free Remission, and Therapeutic Vulnerabilities
title_sort bone marrow immune microenvironment in cml: treatment responses, treatment-free remission, and therapeutic vulnerabilities
topic Chronic Myeloid Leukemias (V Oehler, Section Editor)
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9995533/
https://www.ncbi.nlm.nih.gov/pubmed/36780103
http://dx.doi.org/10.1007/s11899-023-00688-6
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