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The bone marrow microenvironment in patients with neuroblastoma: presence of IFN signature and significant down-regulation of CXCL12 expression

ABSTRACT: Neuroblastoma (NB) is the most common extra cranial solid tumor in infants. Although several risk factors including patient age, disease stage and genetic abnormalities, such as MYCN amplification and 11q deletion, have been shown to predict outcome, the mechanisms responsible for the heterogeneous clinical behavior of this tumor, ranging from spontaneous regression to rapid progression of disease and patient’s death, remain largely unknown. Patients with disseminated disease mainly show metastasis at bone marrow (BM) and bone. The presence of metastasis is an independent unfavorable prognostic factor for NB patients over 18 months of age at diagnosis, whose event-free and overall survivals are grim despite intensive multimodal therapies. We decided to investigate the transcriptome of both NB metastatic cells and resident hematopoietic BM cells to get insight on potential targets for diagnostic, prognostic and therapeutic purposes. Hereby, we report on the results obtained by comparing BM resident hematopoietic cells in the presence and absence of infiltrating NB hematopoietic cells with BM cells from young healthy donors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE25624 | GEO | 2011/09/30

SECONDARY ACCESSION(S): PRJNA133975

REPOSITORIES: GEO

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Project description:Neuroblastoma (NB) is a pediatric tumor with a heterogeneous presentation at diagnosis. Fifty per cent of patients present with localized disease (stage L1/L2) whereas the other half have metastatic disease (stage M), mainly involving the bone marrow (BM). In these latter patients the physical occupancy of the BM space by metastatic NB cells has been thought to be responsible for impairment of BM function. Here, based on gene expression profiles of BM resident cells obtained in a large number of stage L and stage M NB patients, as compared to gene expression profiles of BM resident cells from healthy subjects, we investigated whether the tumor growth, either at distance or locally, affected hematopoietic lineages' maturation and release of mature hematopoietic cells in the periphery (PB). Our investigation clearly demonstrated that in children with NB, regardless of the presence of metastatic cells in the BM, there was a selective impairment of erythrocyte maturation at the ortho-chromic stage. In the BM, all the other cell lineages were un-affected. The altered erythrocyte maturation resulted in a reduced amount, and increased RWD, of PB erythrocytes. In PB samples from patients with stage L disease a significant increase in the number of mature neutrophils was observed, suggesting that in these NB patients innate immunity was activated. No increase occurred in PB of stage M NB patients. Although the cause of the selective impairment of erythrocyte maturation, as well as that of the activation of innate immunity in stage L NB patients remained elusive, our observations allowed to fully refusing the tenet that BM-infiltrating NB cells affected physiological BM functions due to physical occupancy of the BM space. In addition, these findings open the way to a new area of research not only in NB and other clinically similar pediatric cancers, such as rhabdos and sarcomas, but also in adult cancers metastasizing in the BM. Looking more carefully to the BM microenvironment could help discovering novel targets for innovative therapeutic approaches.

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The bone marrow microenvironment in patients with neuroblastoma: presence of IFN signature and significant down-regulation of CXCL12 expression

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