The age of the bone marrow microenvironment influences B-cell acute lymphoblastic leukemia progression via CXCR5-CXCL13.
Costanza ZanettiDaniela S Krause
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 ...Continue Reading
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