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

Paola Scaruffi, Fabio Morandi, Fabio Gallo, Sara Stigliani, Stefano Parodi, Stefano Moretti, Stefano Bonassi, Paolo Fardin, Alberto Garaventa, Giulio Zanazzo, Vito Pistoia, Gian Paolo Tonini, Maria Valeria Corrias

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)44-51
Number of pages8
JournalPediatric Blood and Cancer
Volume59
Issue number1
DOIs
Publication statusPublished - Jul 15 2012

Keywords

  • Bone marrow microenvironment
  • CXCL12
  • Gene expression profiling
  • IFN signature
  • Metastasis
  • Neuroblastoma

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology

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