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000170402 1001_ $$aZanetti, Costanza$$b0
000170402 245__ $$aThe age of the bone marrow microenvironment influences B-cell acute lymphoblastic leukemia progression via CXCR5-CXCL13.
000170402 260__ $$aWashington, DC$$bAmerican Society of Hematology$$c2021
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000170402 520__ $$aB-cell acute lymphoblastic leukemia (B-ALL) occurs most commonly in children, while chronic myeloid leukemia (CML) is more frequent in adults. The myeloid bias of hematopoiesis in elderly individuals has been considered causative, but the age of the bone marrow (BM) microenvironment (BMM) may be contributory. Using various murine models of B-ALL in young versus old mice, we recapitulated B-ALL preponderance in children versus adults. We showed differential effects of young versus old BM macrophages on B-ALL cell function. Molecular profiling using RNA- and ATAC-seq revealed pronounced differences in young versus old BMM-derived macrophages and enrichment for gene sets associated with inflammation. In concordance with the role of C-X-C motif chemokine (CXCL) 13 for disease-associated B cell chemoattraction, we found CXCL13 to be highly expressed in young macrophages on a translational compared to a transcriptional level. Inhibition of CXCL13 in BM macrophages impaired leukemia cell migration and decreased the proliferation of cocultured B-ALL cells, while recombinant CXCL13 increased pAKT and B-ALL cell expansion. Pretreatment of B-ALL-initiating cells with CXCL13 accelerated B-ALL progression. Deficiency of Cxcr5, the receptor for CXCL13, on B-ALL-initiating cells prolonged murine survival, while high expression of CXCR5 in pediatric B-ALL may predict central nervous system relapse. CXCL13 staining was increased in bone sections from pediatric compared to adult B-ALL patients. Taken together, our study shows that the age of the BMM and, in particular, BM macrophages influence the leukemia phenotype. The CXCR5-CXCL13-axis may act as prognostic marker and an attractive novel target for the treatment of B-ALL.
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000170402 7001_ $$aKumar, Rahul$$b1
000170402 7001_ $$aEnder, Joscha$$b2
000170402 7001_ $$aGodavarthy, Parimala S$$b3
000170402 7001_ $$0P:(DE-He78)6bd32b26ed14ffc9746ba2d4816e0559$$aHartmann, Mark$$b4$$udkfz
000170402 7001_ $$0P:(DE-He78)198a73f54b40192a2fdc2bf53ba7ca27$$aHey, Joschka$$b5$$udkfz
000170402 7001_ $$0P:(DE-He78)75efcd61c13c2fbe457cdf3454ef486c$$aBreuer, Kersten$$b6$$udkfz
000170402 7001_ $$aWeissenberger, Eva S$$b7
000170402 7001_ $$00000-0002-9296-9403$$aMinciacchi, Valentina R$$b8
000170402 7001_ $$00000-0002-2161-914X$$aKarantanou, Christina$$b9
000170402 7001_ $$00000-0003-1581-1327$$aGu, Zhaohui$$b10
000170402 7001_ $$aRoberts, Kathryn G$$b11
000170402 7001_ $$00000-0002-4523-1676$$aMetzler, Markus$$b12
000170402 7001_ $$aStock, Wendy$$b13
000170402 7001_ $$00000-0002-1871-1850$$aMullighan, Charles G$$b14
000170402 7001_ $$aBloomfield, Clara D$$b15
000170402 7001_ $$aFilmann, Natalie$$b16
000170402 7001_ $$aBankov, Katrin$$b17
000170402 7001_ $$00000-0003-3424-1091$$aHartmann, Sylvia$$b18
000170402 7001_ $$00000-0002-7753-0697$$aHasserjian, Robert P$$b19
000170402 7001_ $$00000-0003-1516-2515$$aCousins, Antony F$$b20
000170402 7001_ $$00000-0001-5449-5246$$aHalsey, Christina$$b21
000170402 7001_ $$0P:(DE-He78)4301875630bc997edf491c694ae1f8a9$$aPlass, Christoph$$b22$$udkfz
000170402 7001_ $$0P:(DE-He78)c403a040c97f91902a7d31b93859f9fc$$aLipka, Daniel$$b23$$udkfz
000170402 7001_ $$00000-0003-3603-1119$$aKrause, Daniela S$$b24
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