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Bone marrow of neuroblastoma patients shows downregulation of CXCL12 expression and presence of IFN signature

Parodi, Stefano; Moretti, Stefano; Garaventa, Alberto; Zanazzo, Giulio; Bonassi, Stefano; Fardin, Paolo; Pistoia, Vito; Tonini, Paolo; Corrias, Maria Valeria; Morandi, Fabio; Gallo, Fabio; Scaruffi, Paola; Stigliani, Sara (2012), Bone marrow of neuroblastoma patients shows downregulation of CXCL12 expression and presence of IFN signature, Pediatric Blood & Cancer, 59, 1, p. 44-51. http://dx.doi.org/10.1002/pbc.23339

Type
Article accepté pour publication ou publié
Date
2012
Journal name
Pediatric Blood & Cancer
Volume
59
Number
1
Publisher
Wiley
Pages
44-51
Publication identifier
http://dx.doi.org/10.1002/pbc.23339
Metadata
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Author(s)
Parodi, Stefano
Moretti, Stefano cc
Garaventa, Alberto
Zanazzo, Giulio
Bonassi, Stefano
Fardin, Paolo
Pistoia, Vito
Tonini, Paolo
Corrias, Maria Valeria
Morandi, Fabio
Gallo, Fabio
Scaruffi, Paola
Stigliani, Sara
Abstract (EN)
Background At diagnosis, children with neuroblastoma (NB) present with either localized or metastatic disease. Since the mechanisms responsible for BM invasion are not well known, we investigated the transcriptome of resident BM cells from NB patients as compared to healthy children. Procedure Ninety-two and 88 children with localized and metastatic NB, respectively, and 15 healthy children were included in the study. BM resident cells recovered from BM aspirates by immunomagnetic bead manipulation were subjected to genome-wide microarray analysis. After validation in an independent set of samples, the genes significantly modulated in resident BM cells from NB patients were tested for their diagnostic/prognostic values. Results BM resident cells, irrespective of neoplastic cell invasion, significantly overexpressed genes involved in innate immune responses, and interferon (IFN) and IFN-DRS signatures were enriched. Genes coding for metallothioneins and zinc finger proteins, and involved in histone and nucleosome/chromatin organization were also overexpressed. Resident BM cells from NB patients significantly downregulated genes involved in cell adhesion, and in erythrocyte, myeloid, and platelet differentiation pathways. Among downregulated genes, CXCL12 expression reached near complete silencing in patients with metastatic disease. The downregulation of CXCL12 expression was independent of contact between NB cell and resident BM cell. Conclusions We demonstrated that NB tumor growth at the primary site can alter the BM microenvironment, and the presence of BM-infiltrating NB cells makes the alterations more pronounced. Therefore, the restoration of a BM physiological state by means of IFN-α monoclonal antibody, Sifalimumab, and selective noradrenaline receptor blockers should be further studied to ameliorate patients' clinical management. Pediatr Blood Cancer 2012; 59: 44–51. © 2011 Wiley Periodicals, Inc.
Subjects / Keywords
neuroblastoma; metastasis; CXCL12; bone marrow microenvironment; IFN signature; gene expression profiling

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