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

Zanetti, C. et al. (2021) The age of the bone marrow microenvironment influences B-cell acute lymphoblastic leukemia progression via CXCR5-CXCL13. Blood, 138(19), pp. 1870-1884. (doi: 10.1182/blood.2021011557) (PMID:34424946)

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, butthe 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 showeddifferential effectsof young versus oldBM macrophageson 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 increasedpAKT 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 andan attractive novel target for the treatment of B-ALL.

• Item Type: Articles
• Additional Information: This work was supported by grant A2016/03 to D.S.K. from the Deutsche Kinderkrebsstiftung and by grants UG1CA233338 and U24CA196171 to C.D.B from NIH/NCI, and The Little Princess Trust grant CCLGA 2017 13 to C.H.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cousins, Dr Antony and Halsey, Professor Chris
• Authors: Zanetti, C., Kumar, R., Ender, J., Godavarthy, P. S., Hartmann, M., Hey, J., Breuer, K., Weissenberger, E. S., Minciacchi, V. R., Karantanou, C., Gu, Z., Roberts, K. G., Metzler, M., Stock, W., Mullighan, C. G., Bloomfield, C. D., Filmann, N., Bankov, K., Hartmann, S., Hasserjian, R. P., Cousins, A. F., Halsey, C., Plass, C., Lipka, D. B., and Krause, D. S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Blood
• Publisher: American Society of Hematology
• ISSN: 0006-4971
• ISSN (Online): 1528-0020
• Published Online: 23 August 2021
• Copyright Holders: Copyright © 2021 The American Society of Hematology
• First Published: First published in Blood 138(19):1870–1884
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
174318		Developing Leukaemic Biomarkers to Enable Personalised CNS-directed Therapy	Christina Halsey	Children's Cancer and Leukaemia Group (CCLG) (CCANLEUG)	CCLGA 2017 13	Institute of Cancer Sciences