title: Stromal niche communalities underscore the contribution of the matricellular protein SPARC to B-cell development and lymphoid malignancies.
abstract: Neoplastic B-cell clones commonly arise within secondary lymphoid organs (SLO). However, during disease progression, lymphomatous cells may also colonize the bone marrow (BM), where they localize within specialized stromal niches, namely the osteoblastic and the vascular niche, according to their germinal center- or extra-follicular-derivation, respectively. We hypothesized the existence of common stromal motifs in BM and SLO B-cell lymphoid niches involved in licensing normal B-cell development as well as in fostering transformed B lymphoid cells. Thus, we tested the expression of prototypical mesenchymal stromal cell (MSC) markers and regulatory matricellular proteins in human BM and SLO under physiologically unperturbed conditions and during B-cell lymphoma occurrence. We identified common stromal features in the BM osteoblastic niche and SLO germinal center (GC) microenvironments, traits that were also enriched within BM infiltrates of GC-associated B-cell lymphomas, suggesting that stromal programs involved in central and peripheral B-cell lymphopoiesis are also involved in malignant B-cell nurturing. Among factors co-expressed by stromal elements within these different specialized niches, we identified the pleiotropic matricellular protein secreted protein acidic and rich in cysteine (SPARC). The actual role of stromal SPARC in normal B-cell lymphopoiesis, investigated inSparc-/-mice and BM chimeras retaining theSparc-/-genotype in host stroma, demonstrated defective BM and splenic B-cell lymphopoiesis. Moreover, in theTrp53knockout (KO) lymphoma model,p53-/-/Sparc-/-double-KO mice displayed impaired spontaneous splenic B-cell lymphomagenesis and reduced neoplastic clone BM infiltration in comparison with theirp53-/-/Sparc+/+counterparts. Our results are among the first to demonstrate the existence of common stromal programs regulating both the BM osteoblastic niche and the SLO GC lymphopoietic functions potentially fostering the genesis and progression of B-cell malignancies.
authors.affiliation: Molecular Immunology Unit; Department of Experimental Oncology and Molecular Medicine; Fondazione IRCCS Istituto Nazionale Tumori; Milan, Italy.
authors.forename: Sabina
authors.initials: S
authors.lastname: Sangaletti
authors.affiliation: Tumor Immunology Unit, Department of Health Sciences; University of Palermo; Palermo, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Tripodo
authors.affiliation: Molecular Immunology Unit; Department of Experimental Oncology and Molecular Medicine; Fondazione IRCCS Istituto Nazionale Tumori; Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Portararo
authors.affiliation: Functional Genomics Core Facility; Department of Experimental Oncology and Molecular Medicine; Fondazione IRCCS Istituto Nazionale Tumori; Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Dugo
authors.affiliation: Molecular Immunology Unit; Department of Experimental Oncology and Molecular Medicine; Fondazione IRCCS Istituto Nazionale Tumori; Milan, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Vitali
authors.affiliation: Molecular Immunology Unit; Department of Experimental Oncology and Molecular Medicine; Fondazione IRCCS Istituto Nazionale Tumori; Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Botti
authors.affiliation: Tumor Immunology Unit, Department of Health Sciences; University of Palermo; Palermo, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Guarnotta
authors.affiliation: Molecular Immunology Unit; Department of Experimental Oncology and Molecular Medicine; Fondazione IRCCS Istituto Nazionale Tumori; Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cappetti
authors.affiliation: Tumor Immunology Unit, Department of Health Sciences; University of Palermo; Palermo, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gulino
authors.affiliation: Molecular Immunology Unit; Department of Experimental Oncology and Molecular Medicine; Fondazione IRCCS Istituto Nazionale Tumori; Milan, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Torselli
authors.affiliation: Molecular Therapies Unit; Department of Experimental Oncology and Molecular Medicine; Fondazione IRCCS Istituto Nazionale Tumori; Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Casalini
authors.affiliation: Molecular Immunology Unit; Department of Experimental Oncology and Molecular Medicine; Fondazione IRCCS Istituto Nazionale Tumori; Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Chiodoni
authors.affiliation: Molecular Immunology Unit; Department of Experimental Oncology and Molecular Medicine; Fondazione IRCCS Istituto Nazionale Tumori; Milan, Italy.
authors.forename: Mario P
authors.initials: MP
authors.lastname: Colombo
keywords: B cell development; SPARC; bone marrow niches; lymphomas; microenvironment
references.citation: Immunity. 2001 Aug;15(2):323-34
references.pmid: 11520466
references.citation: Am J Pathol. 1999 Mar;154(3):805-12
references.pmid: 10079258
references.citation: J Immunol. 1984 Jan;132(1):332-9
references.pmid: 6606670
references.citation: Nat Rev Clin Oncol. 2011 Mar 29;8(8):456-66
references.pmid: 21448151
references.citation: Blood. 2014 Mar 20;123(12):1836-49
references.pmid: 24452203
references.citation: Nat Immunol. 2011 Dec 25;13(2):170-80
references.pmid: 22197976
references.citation: J Immunol. 2014 Mar 1;192(5):2449-59
references.pmid: 24501201
references.citation: J Exp Med. 2003 Nov 17;198(10):1475-85
references.pmid: 14610043
references.citation: Hematology Am Soc Hematol Educ Program. 2007;:210-5
references.pmid: 18024632
references.citation: Methods Mol Biol. 2004;271:37-58
references.pmid: 15146111
references.citation: Curr Cancer Drug Targets. 2009 Aug;9(5):617-25
references.pmid: 19508173
references.citation: Immunity. 2010 Feb 26;32(2):187-99
references.pmid: 20171124
references.citation: J Cell Biol. 2012 Feb 20;196(4):395-406
references.pmid: 22351925
references.citation: Blood. 2013 Jun 13;121(24):4821-31
references.pmid: 23589674
references.citation: J Immunol. 2005 Feb 1;174(3):1438-45
references.pmid: 15661902
references.citation: Blood. 1993 Mar 1;81(5):1323-32
references.pmid: 8443393
references.citation: J Leukoc Biol. 2008 Apr;83(4):799-803
references.pmid: 18063695
references.citation: J Immunol. 2001 May 1;166(9):5567-77
references.pmid: 11313396
references.citation: J Exp Med. 1989 Jul 1;170(1):333-8
references.pmid: 2787384
references.citation: J Exp Med. 2000 Jan 3;191(1):5-8
references.pmid: 10620600
references.citation: Blood. 1999 Dec 1;94(11):3658-67
references.pmid: 10572077
references.citation: Blood. 2002 Jul 1;100(1):246-58
references.pmid: 12070034
references.citation: Blood. 2009 Jul 2;114(1):49-59
references.pmid: 19417209
references.citation: Blood. 1998 Aug 1;92(3):894-900
references.pmid: 9680357
references.citation: Blood. 1997 May 1;89(9):3385-95
references.pmid: 9129046
references.citation: Adv Hematol. 2012;2012:138079
references.pmid: 22400028
references.citation: J Immunol. 2003 Jan 1;170(1):252-60
references.pmid: 12496407
references.citation: Proc Natl Acad Sci U S A. 2013 Jul 30;110(31):E2915-24
references.pmid: 23847204
references.citation: Blood. 2012 Oct 25;120(17):3541-54
references.pmid: 22955913
references.citation: Acta Haematol. 2007;117(1):48-50
references.pmid: 17095859
references.citation: Nature. 2013 Mar 14;495(7440):227-30
references.pmid: 23434756
references.citation: J Immunol. 2004 May 1;172(9):5535-43
references.pmid: 15100296
references.citation: J Cell Sci. 2006 Jan 15;119(Pt 2):314-25
references.pmid: 16390867
references.citation: Blood. 2011 Mar 31;117(13):3596-608
references.pmid: 21245480
references.citation: Cancer Metastasis Rev. 2010 Jun;29(2):295-307
references.pmid: 20386958
references.citation: Br J Haematol. 2006 Sep;134(5):467-74
references.pmid: 16848793
references.citation: Nat Rev Immunol. 2009 Nov;9(11):767-77
references.pmid: 19855403
references.citation: Am J Pathol. 2011 Dec;179(6):3000-10
references.pmid: 22001347
references.citation: Cancer Discov. 2014 Jan;4(1):110-29
references.pmid: 24189145
references.citation: Annu Rev Immunol. 2001;19:595-621
references.pmid: 11244048
references.citation: Cancer Res. 2008 Nov 1;68(21):9050-9
references.pmid: 18974151
references.citation: J Autoimmun. 2011 Dec;37(4):300-10
references.pmid: 21962567