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@ARTICLE{Zanetti:170402,
      author       = {C. Zanetti and R. Kumar and J. Ender and P. S. Godavarthy
                      and M. Hartmann$^*$ and J. Hey$^*$ and K. Breuer$^*$ and E.
                      S. Weissenberger and V. R. Minciacchi and C. Karantanou and
                      Z. Gu and K. G. Roberts and M. Metzler and W. Stock and C.
                      G. Mullighan and C. D. Bloomfield and N. Filmann and K.
                      Bankov and S. Hartmann and R. P. Hasserjian and A. F.
                      Cousins and C. Halsey and C. Plass$^*$ and D. Lipka$^*$ and
                      D. S. Krause},
      title        = {{T}he age of the bone marrow microenvironment influences
                      {B}-cell acute lymphoblastic leukemia progression via
                      {CXCR}5-{CXCL}13.},
      journal      = {Blood},
      volume       = {138},
      number       = {19},
      issn         = {1528-0020},
      address      = {Washington, DC},
      publisher    = {American Society of Hematology},
      reportid     = {DKFZ-2021-01909},
      pages        = {1870-1884},
      year         = {2021},
      note         = {2021 Nov 11;138(19):1870-1884},
      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.},
      cin          = {B370 / B340 / W620},
      ddc          = {610},
      cid          = {I:(DE-He78)B370-20160331 / I:(DE-He78)B340-20160331 /
                      I:(DE-He78)W620-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34424946},
      doi          = {10.1182/blood.2021011557},
      url          = {https://inrepo02.dkfz.de/record/170402},
}