NB,3 a solid tumor of early childhood, derives from the embryonicneural crest. In vitro (1) and in vivo (2) NB cells frequently maintain theability to differentiate along pathways reminiscent of their embryonicorigin (1). The differentiation potential of the tumor cells is probablyrelated to the clinical outcome, which varies from aggressive and gener-ally fatal to spontaneous regression (3). Several clinical, biological, andgenetic parameters have been used to assess the prognosis and to help theclinician in devising the most effective therapies for NB patients. Age (1),tumor staging (4), and ferritin (5) and lactate dehydrogenase (6) serumlevels are presently used for these purposes. Among the genetic charac-teristics, MYCN amplification (7) as well as the deletion of the short armof chromosome 1, where one or more tumor suppressor genes are thoughtto be located (8), define a group of patients at high risk. The expressionof trkA and low-affinity nerve growth factor receptor have been associ-ated with a benign outcome. Accordingly, the absence of these receptorswas linked to a more aggressive disease (9).Although these clinical and molecular features have been associ-ated with disease outcome, their interrelationship and their impact inthe context of known risk factors is not always clear. For instance, thedeletion of the short arm of chromosome 1 is a risk factor if associatedwith the amplification of MYCN but, when present alone, does notcorrelate with an adverse prognosis (10). On the contrary, MYCNamplification has been demonstrated to contribute significantly to riskestimation and constitutes by far the most useful genetic indicator(11). Nevertheless, the predictive value of MYCN amplification isalso incomplete because this genetic trait is present only in a fractionof patients with poor outcome. Thus, the identification of new inde-pendent prognostic indicators that may broaden the predictive value,thus far provided by a well-recognized marker such as MYCN am-plification, is strongly needed in human NB.The myb genes are crucial for the control of proliferation anddifferentiation in a number of cell types including NB cells (12–15).We and others have assessed the functional significance of myb genesexpression in NB cells in vitro (14, 15). The expression of c-myb, atranscriptional regulator essential for the proliferation of hematopoi-etic cells (16), is down-regulated in NB cell lines during differentia-tion (15). RNA and DNA antisense experiments have demonstratedthat inhibition of c-myb mRNA impairs the proliferation (17), andincreases the susceptibility, of NB cells to apoptosis in vitro (18).B-myb is also expressed in NB cells and, like c-myb, is down-regulated during differentiation (19). In addition, when constitutivelyexpressed, it inhibits differentiation of NB cell lines (19). A-mybexpression was also detected in NB cells (20), but much less is knownabout its regulation and functional significance. Together, these find-ings prompted us to investigate whether the expression of myb genesin NB tumors correlates with disease stage and prognosis.

Expression of B-myb in neuroblastoma tumors is a poor prognostic factor independent from MYCN amplification / Raschella, G; Cesi, V; Amendola, R; Negroni, A; Tanno, B; Altavista, P; Tonini, Gp; DE BERNARDI, B; Calabretta, Bruno. - In: CANCER RESEARCH. - ISSN 0008-5472. - STAMPA. - 59:(1999), pp. 3365-3368.

Expression of B-myb in neuroblastoma tumors is a poor prognostic factor independent from MYCN amplification

CALABRETTA, Bruno
1999

Abstract

NB,3 a solid tumor of early childhood, derives from the embryonicneural crest. In vitro (1) and in vivo (2) NB cells frequently maintain theability to differentiate along pathways reminiscent of their embryonicorigin (1). The differentiation potential of the tumor cells is probablyrelated to the clinical outcome, which varies from aggressive and gener-ally fatal to spontaneous regression (3). Several clinical, biological, andgenetic parameters have been used to assess the prognosis and to help theclinician in devising the most effective therapies for NB patients. Age (1),tumor staging (4), and ferritin (5) and lactate dehydrogenase (6) serumlevels are presently used for these purposes. Among the genetic charac-teristics, MYCN amplification (7) as well as the deletion of the short armof chromosome 1, where one or more tumor suppressor genes are thoughtto be located (8), define a group of patients at high risk. The expressionof trkA and low-affinity nerve growth factor receptor have been associ-ated with a benign outcome. Accordingly, the absence of these receptorswas linked to a more aggressive disease (9).Although these clinical and molecular features have been associ-ated with disease outcome, their interrelationship and their impact inthe context of known risk factors is not always clear. For instance, thedeletion of the short arm of chromosome 1 is a risk factor if associatedwith the amplification of MYCN but, when present alone, does notcorrelate with an adverse prognosis (10). On the contrary, MYCNamplification has been demonstrated to contribute significantly to riskestimation and constitutes by far the most useful genetic indicator(11). Nevertheless, the predictive value of MYCN amplification isalso incomplete because this genetic trait is present only in a fractionof patients with poor outcome. Thus, the identification of new inde-pendent prognostic indicators that may broaden the predictive value,thus far provided by a well-recognized marker such as MYCN am-plification, is strongly needed in human NB.The myb genes are crucial for the control of proliferation anddifferentiation in a number of cell types including NB cells (12–15).We and others have assessed the functional significance of myb genesexpression in NB cells in vitro (14, 15). The expression of c-myb, atranscriptional regulator essential for the proliferation of hematopoi-etic cells (16), is down-regulated in NB cell lines during differentia-tion (15). RNA and DNA antisense experiments have demonstratedthat inhibition of c-myb mRNA impairs the proliferation (17), andincreases the susceptibility, of NB cells to apoptosis in vitro (18).B-myb is also expressed in NB cells and, like c-myb, is down-regulated during differentiation (19). In addition, when constitutivelyexpressed, it inhibits differentiation of NB cell lines (19). A-mybexpression was also detected in NB cells (20), but much less is knownabout its regulation and functional significance. Together, these find-ings prompted us to investigate whether the expression of myb genesin NB tumors correlates with disease stage and prognosis.
59
3365
3368
Expression of B-myb in neuroblastoma tumors is a poor prognostic factor independent from MYCN amplification / Raschella, G; Cesi, V; Amendola, R; Negroni, A; Tanno, B; Altavista, P; Tonini, Gp; DE BERNARDI, B; Calabretta, Bruno. - In: CANCER RESEARCH. - ISSN 0008-5472. - STAMPA. - 59:(1999), pp. 3365-3368.
Raschella, G; Cesi, V; Amendola, R; Negroni, A; Tanno, B; Altavista, P; Tonini, Gp; DE BERNARDI, B; Calabretta, Bruno
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