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

Author:

Zanetti Costanza1ORCID,Kumar Rahul1ORCID,Ender Joscha1,Godavarthy Parimala S.2,Hartmann Mark34ORCID,Hey Joschka567ORCID,Breuer Kersten34ORCID,Weissenberger Eva S.1,Minciacchi Valentina R.1ORCID,Karantanou Christina1ORCID,Gu Zhaohui8ORCID,Roberts Kathryn G.8,Metzler Markus9ORCID,Stock Wendy10,Mullighan Charles G.8ORCID,Bloomfield Clara D.11,Filmann Natalie12,Bankov Katrin13,Hartmann Sylvia13ORCID,Hasserjian Robert P.14ORCID,Cousins Antony F.15ORCID,Halsey Christina15ORCID,Plass Christoph16,Lipka Daniel B.3417ORCID,Krause Daniela S.118192021ORCID

Affiliation:

1. Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany;

2. Department of Internal Medicine II, Hematology, Oncology, University Hospital Tübingen, Tübingen, Germany;

3. Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany;

4. National Center for Tumor Diseases (NCT), Heidelberg, Germany;

5. Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany;

6. German-Israeli Helmholtz Research School in Cancer Biology, Heidelberg, Germany;

7. Faculty of Biosciences, Ruprecht Karls University of Heidelberg, Heidelberg, Germany;

8. Department of Pathology, St Jude Children's Research Hospital, Memphis, TN;

9. Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany;

10. Department of Hematology and Oncology, University of Chicago, Chicago, IL;

11. The Ohio State University Comprehensive Cancer Center, Columbus, OH;

12. Institute of Biostatistics and Mathematical Modeling, and

13. Department of Pathology, Goethe University, Frankfurt am Main, Germany;

14. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA;

15. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom;

16. Cancer Epigenetics Group, Division of Epigenomics and Cancer Risk Factors, DKFZ, Heidelberg, Germany;

17. Faculty of Medicine, Otto von Guericke University, Magdeburg, Germany;

18. DKFZ, Heidelberg, Germany;

19. German Cancer Consortium (DKTK), Heidelberg, Germany;

20. Frankfurt Cancer Institute, Frankfurt am Main, Germany; and

21. Faculty of Medicine, Goethe University, Frankfurt am Main, Germany

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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