Journal Article

DKFZ-2021-01909

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The age of the bone marrow microenvironment influences B-cell acute lymphoblastic leukemia progression via CXCR5-CXCL13.

Zanetti, C. ; Kumar, R. ; Ender, J. ; Godavarthy, P. S. ; Hartmann, M.DKFZ* ; Hey, J.DKFZ* ; Breuer, K.DKFZ* ; 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.DKFZ* ; Lipka, D.DKFZ* ; Krause, D. S.

2021
American Society of Hematology Washington, DC

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Please use a persistent id in citations: doi:10.1182/blood.2021011557

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.

Note: 2021 Nov 11;138(19):1870-1884

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Contributing Institute(s):

1. Epigenomik (B370)
2. Translationale Medizinische Onkologie (B340)
3. German Human GEnome-Phenome Archive (W620)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2021

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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