Altered erythropoiesis and decreased number of erythrocytes in children with neuroblastoma

Abstract

Neuroblastoma (NB) is a pediatric tumor presenting at diagnosis either as localized or metastatic disease, which mainly involves the bone marrow (BM). The physical occupancy of BM space by metastatic NB cells has been held responsible for impairment of BM function. Here, we investigated whether localized or metastatic NB may alter hematopoietic lineages’ maturation and release of mature cells in the periphery, through gene expression profiling, analysis of BM smears, cell blood count and flow cytometry analysis.Gene ontology and disease-associated analysis of the genes significantly under-expressed in BM resident cells from children with localized and metastatic NB, as compared to healthy children, indicated anemia, blood group antigens, and heme and porphyrin biosynthesis as major functional annotation clusters. Accordingly, in children with NB there was a selective impairment of erythrocyte maturation at the ortho-chromic stage that resulted in reduced erythrocyte count in the periphery, regardless of the presence of metastatic cells in the BM. By considering all NB patients, low erythrocyte count at diagnosis associated with worse survival. Moreover, in the subset of metastatic patients, low erythrocyte count, hemoglobin and hematocrit and high red cell distribution width at follow-up also associated with worse outcome.These observations provide an alternative model to the tenet that infiltrating cells inhibit BM functions due to physical occupancy of space and may open a new area of research in NB to understand the mechanism(s) responsible for such selective impairment.

Microvesicles expressing adenosinergic ectoenzymes and their potential role in modulating bone marrow infiltration by neuroblastoma cells

“…37 Reports indicate that NB infiltration may affect the phenotype and function of BM-resident cells. 10,38,39 The results of the present study show that both metastatic NB cells and NB cell lines express adenosinergic ectoenzymes, thus NB cells may contribute themselves to ADO production in the BM microenvironment. Moreover, BM infiltration by metastatic NB cells is paralleled by an altered expression of ectoenzymes on resident BM cell populations.…”

Monitoring Immune Responses in Neuroblastoma Patients during Therapy

“…Leukocyte counts have found to be significantly higher in NBL patients compared to controls [38]. Although no difference is observed in total lymphocyte count between healthy controls, localized, and metastatic patients, relative numbers of multiple lymphocyte subsets do vary [31].…”

miRNA expression profile of bone marrow resident cells from children with neuroblastoma is not significantly different from that of healthy children

“…Since only miR-221 over-expression occurred in all patients with NB regardless of presence of metastatic cells in the BM as it is the case of altered erythrocyte maturation [ 17 ], we extracted the lists of genes potentially targeted by miR-221 from three different miRNA databases, Targetscan, miRanda and PicTar. In fact, TargetScan predicts biological targets of miRNAs by searching for the presence of conserved 8mer, 7mer, and 6mer sites that match the seed region of each miRNA [ 21 ] ( http://www.targetscan.org ); PicTar uses an algorithm to provide details, such as 3′ UTR alignments with predicted sites and links to various public databases [ 22 ] ( http://pictar.mdc-berlin.de ), and miRanda prediction algorithm optimizes sequence complementarity using position-specific rules and relies on strict requirements of interspecies conservation [ 23 ] ( http://www.microrna.org/microrna/home.do ).…”

“…Recently, we showed that in children with NB erythrocyte maturation was selectively impaired at the ortho-chromic stage, regardless of the presence of metastatic cells in the BM [ 17 ]. Among the genes significantly under-expressed by BM resident cells from children with NB, as compared with healthy children, we identified a set involved in heme and porphyrin biosynthesis in the mitochondria [ 17 ].…”

“…Recently, we showed that in children with NB erythrocyte maturation was selectively impaired at the ortho-chromic stage, regardless of the presence of metastatic cells in the BM [ 17 ]. Among the genes significantly under-expressed by BM resident cells from children with NB, as compared with healthy children, we identified a set involved in heme and porphyrin biosynthesis in the mitochondria [ 17 ]. Given the pivotal role of miRNAs in regulating gene expression, here we investigated whether the decreased expression of these genes was regulated by specific miRNA(s) over-expressed by BM resident cells of children with NB, as compared with healthy children.…”