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. 

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

Leukemia is a malignant tumor with high heterogeneity and a complex evolutionary process. It is difficult to resolve the heterogeneity and clonal evolution of leukemia cells by applying traditional bulk sequencing techniques, thus preventing a deep understanding of the mechanisms of leukemia development and the identification of potential therapeutic targets. However, with the development and application of single-cell sequencing technology, it is now possible to investigate the gene expression profile, mutations, and epigenetic features of leukemia at the single-cell level, thus providing a new perspective for leukemia research. In this article, we review the recent applications and advances of single-cell sequencing technology in leukemia research, discuss its potential for enhancing our understanding of the mechanisms of leukemia development, discovering therapeutic targets and personalized treatment, and provide reference guidelines for the significance of this technology in clinical research.

Application and research progress of single cell sequencing technology in leukemia

Abstract This study was to explore the role of NK cell subsets and gene expression in maintaining TFR status. We identified six types of NK cells in the PBMCs over both groups (healthy controls and patients with TFR). Gene Oncology analysis showed that up regulated genes were enriched in the categories of “immune response,” “reaction to tumor cells,” and “cytolysis.” In addition, we found that the three NK cell subsets, mature and terminal NK cells, CD56 bright NK cells, and transitional NK cells, contained many significantly up regulated genes in both groups, and that CD56 bright NK cells and transitional NK cells in patients with CML-TFR were in a proliferating and activated state. Through single-cell RNA sequencing analysis, we confirmed that the mature and terminal, CD56 bright, and transitional subsets of NK cells play an indispensable role in maintaining TFR in patients with CML.

Single-cell RNA sequencing to explore composition of peripheral blood NK cells in patients with chronic myeloid leukemia in treatment-free remission

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Single-cell RNA sequencing to explore composition of peripheral blood NK cells in patients with chronic myeloid leukemia in treatment-free remission