The age of the bone marrow microenvironment influences B-cell acute lymphoblastic leukemia progression via CXCR5-CXCL13

Abstract

B-cell acute lymphoblastic leukemia (B-ALL) occurs most commonly in children, while chronic myeloid leukemia (CML) is more frequent in adults. The myeloid bias of hematopoiesis in elderly individuals has been considered causative, but the age of the bone marrow (BM) microenvironment (BMM) may be contributory. Using various murine models of B-ALL in young versus old mice, we recapitulated B-ALL preponderance in children versus adults. We showed differential effects of young versus old BM macrophages on B-ALL cell function. Molecular profiling using RNA- and ATAC-seq revealed pronounced differences in young versus old BMM-derived macrophages and enrichment for gene sets associated with inflammation. In concordance with the role of C-X-C motif chemokine (CXCL) 13 for disease-associated B cell chemoattraction, we found CXCL13 to be highly expressed in young macrophages on a translational compared to a transcriptional level. Inhibition of CXCL13 in BM macrophages impaired leukemia cell migration and decreased the proliferation of cocultured B-ALL cells, while recombinant CXCL13 increased pAKT and B-ALL cell expansion. Pretreatment of B-ALL-initiating cells with CXCL13 accelerated B-ALL progression. Deficiency of Cxcr5, the receptor for CXCL13, on B-ALL-initiating cells prolonged murine survival, while high expression of CXCR5 in pediatric B-ALL may predict central nervous system relapse. CXCL13 staining was increased in bone sections from pediatric compared to adult B-ALL patients. Taken together, our study shows that the age of the BMM and, in particular, BM macrophages influence the leukemia phenotype. The CXCR5-CXCL13-axis may act as prognostic marker and an attractive novel target for the treatment of B-ALL.

Potential Role of CXCL13/CXCR5 Signaling in Immune Checkpoint Inhibitor Treatment in Cancer

“…CD8 + and CD4 + T cells, cancer-associated fibroblasts, cancer cells, and dendritic cells are able to secrete CXCL13, and CD8 + and CD4 + T cells, B cells, and cancer cells express CXCR5 ( Figure 2 ). Increasing research has reported the detection of CXCL13 in the tumor microenvironment of many different types of cancer [ 103 , 104 , 105 , 106 , 107 , 108 , 109 ]. When the cancer microenvironment is enriched in CXCL13, the recruitment of CXCR5-expressing leukocytes to the tumor microenvironment increases.…”

In Vitro and In Vivo Modeling of Normal and Leukemic Bone Marrow Niches: Cellular Senescence Contribution to Leukemia Induction and Progression

“…Specifically, it is a matter of discussion regarding how representative mouse models of hematopoietic aging or leukemia development are and if further modeling should be conducted in aged mice instead of young animals to understand the context dependency of genetic and pharmacological perturbations. This is particularly relevant when discussing murine models for pediatric leukemias, where differential effects of young vs. old mice's BM microenvironment on B-ALL cells can be observed [213]. Concerns about animal welfare, costs, validity and applicability of outcomes when animal models are used must also be taken into consideration; however, applying the most recent biotechnology and technical advances, such as single-cell and high-throughput platforms, will allow for better exploitation of the biological resources.…”

Leukemia Stem Cells as a Potential Target to Achieve Therapy-Free Remission in Chronic Myeloid Leukemia

“…Macrophages in young mice were found to produce higher levels of CXCL13 than those in old mice, and the CXCR5-CXCL13 axis promoted the proliferation of B-ALL cells in a young bone marrow microenvironment. Consistently, Cxcr5 deletion in B-ALL stem cells showed survival advantages in a B-ALL murine model, while high expression of CXCR5 in pediatric B-ALL predicted central nervous system relapse [ 97 ]. These data support the idea that the aging of bone marrow macrophages influences leukemia phenotype and highlight the CXCL13-CXCR5 axis as a potential target for B-ALL therapy.…”

“…CML is rare in childhood but more prevalent among adults, due at least in part to increasing myeloid-biased hematopoiesis with age. Dr. Krause’s group explored the contributions of the aged microenvironment to CML pathogenesis [ 97 ]. C-X-C motif chemokine 13 (CXCL13) is a B cell chemo-attractant secreted by macrophages and is bound by its receptor CXCR5.…”