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

Abstract

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.

A Microchip For Exosome Isolation That Can Be Impregnated With Imatinib Simultaneously: An In Vitro Analysis

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Leukemic Stem Cells and Hematological Malignancies

“…LSCs reside in the bone marrow immune microenvironment [ 89 ]. This microenvironment provides LSCs with protection against apoptosis, provides resistance to leukemia therapy, and circumvents immune responses [ 90 ]. For example, bone marrow stromal cells can stabilize the β-catenin, which is associated with resistance to tyrosine kinase inhibitors used to treat CML [ 91 ].…”

High-throughput formulation of reproducible 3D cancer microenvironments for drug testing in myelogenous leukemia

“…As a result -via enhancing the metabolic plasticity, pro-survival signaling and proliferation of leukemic cells -the bone marrow cells may favor the persistence and progression of leukemia, including the self-renewal capacities of the malignant progenitor cells (Vianello et al, 2010). Overall, the bone marrow microenvironment is known to contribute to myeloid malignancies and protect CML cells from drug-induced cytotoxicity through various routes of intercellular communication (Chen et al, 2021;Dolinska et al, 2023;Joshi et al, 2021;Kolba et al, 2019;Korn and Méndez-Ferrer, 2017;Le et al, 2020;Pal et al, 2022;Patterson and Copland, 2023). For example, immunosuppression and T-cell exhaustion (Swatler et al, 2022b(Swatler et al, , 2022a are promoted in the presence of leukemic extracellular vesicles (EVs).…”