ABSTRACT
B-cell acute lymphoblastic leukemia (B-ALL) occurs most commonly in children, whereas chronic myeloid leukemia is more frequent in adults. The myeloid bias of hematopoiesis in elderly individuals has been considered causative, but the age of the bone marrow microenvironment (BMM) may be contributory. Using various murine models of B-ALL in young vs old mice, we recapitulated B-ALL preponderance in children vs adults. We showed differential effects of young vs old BM macrophages on B-ALL cell function. Molecular profiling using RNA- and ATAC-sequencing revealed pronounced differences in young vs 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 with a transcriptional level. Inhibition of CXCL13 in BM macrophages impaired leukemia cell migration and decreased the proliferation of cocultured B-ALL cells, whereas 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, whereas high expression of CXCR5 in pediatric B-ALL may predict central nervous system relapse. CXCL13 staining was increased in bone sections from pediatric compared with adult patients with B-ALL. 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.
Subject(s)
Chemokine CXCL13/genetics , Gene Expression Regulation, Leukemic , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Receptors, CXCR5/genetics , Tumor Microenvironment , Aging , Animals , Bone Marrow/metabolism , Bone Marrow/pathology , Cell Line, Tumor , Disease Progression , Humans , Mice, Inbred BALB C , Mice, Inbred C57BL , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathologyABSTRACT
It has been shown that it is possible to predict the CD 34+ hematopoietic progenitor cell dose from collection procedures on TerumoBCT COBE Spectra® cell separator platform using simple variables available at the start of the procedure. In this article, we demonstrate that this can be done simply and reliably using TerumoBCT Spectra Optia® ("Optia") cell separator platform with a very close correlation between predicted and actual results (correlation coefficient 0.956). This knowledge can be used to optimize apheresis sessions and to minimize harmful effects and costs. In addition, we have shown differences in collection efficiency between healthy donors and cancer patients undergoing autologous donation. Finally, we have shown a small but significant improvement in collection efficiency for the Optia platform compared with the COBE Spectra platform.