A variety of anti-apoptotic proteins are expressed in different tumors, and their expression levels may be related to the unfavorable features at diagnosis, a poor response to treatment or both. However, the clinical relevance of these biological regulators remains largely elusive, and particularly, there have been no studies on the prognostic relevance of XIAP expression in childhood AML to date, except for the only study by Tamm et al. (15
) who demonstrated that a high level of XIAP expression correlated with a poorer overall survival in childhood AML. From this context, the present study was performed to investigate the possible relationship between XIAP expression and the clinical features in childhood de novo AML.
In the present study, the level of XIAP expression was found to be associated with the clinical characteristics at diagnosis. The level of XIAP expression was higher in patients with extramedullary disease than in those without. In addition, the level of XIAP expression was higher in patients with a high leukocyte count and patients with FLT3
-ITD/TKD mutation than in those without, although the differences were not statistically significant. However, there was no significant difference in the level of XIAP expression according to cytogenetic abnormalities (favorable vs. intermediate/unfavorable), which are known to be the most significant prognostic factor in AML (3
). These findings suggest that XIAP expression is independent of cytogenetic abnormalities in childhood AML.
The early response to induction chemotherapy has proven to play an important role in children with acute lymphoblastic leukemia (ALL) (27
). In childhood ALL, the failure of achieving blast clearance from the bone marrow aspirates after 1 or 2 weeks of induction chemotherapy (27
) or the persistence of circulating blasts after 1 week of multi-agent chemotherapy (29
) indicates a poor prognosis. It is likely that the initial response to induction chemotherapy may also be predictive of the outcome in childhood AML, although there are currently limited data available to draw a definite conclusion. Some studies evaluated the response to induction chemotherapy by assessing the degree of residual leukemic infiltration in the bone marrow after 6 or 14 days of induction chemotherapy (4
). In the present study, the early response to induction chemotherapy was evaluated on day 7, and the unfavorable day 7 response was strongly associated with a worse 3-yr RFS (80.9±15.2% vs. 38.1±28.8%, P
=0.008). Here again, it is of note that the level of XIAP expression was significantly higher in patients with an unfavorable day 7 response than in those without. Similarly, the proportion of patients with an unfavorable day 7 response was higher in patients with XIAP overexpression (≥median) than in those without. These findings were in line with the result of in vitro cytotoxicity assay. In addition, the frequency of induction failure after primary induction chemotherapy due to poor response was higher in patients with XIAP overexpression than in those without, albeit without a statistical significance. These findings suggest that XIAP overexpression is associated with a worse early response to induction chemotherapy. The level of XIAP expression was higher in patients who experienced relapse than in patients who had been in continuous CR. Similarly, the frequency of relapse was higher in patients with XIAP overexpression than in those without. As a result, the 3-yr RFS rate was lower in patients with XIAP overexpression than in those without. In the multivariate analyses, XIAP overexpression was an independent unfavorable prognostic factor for RFS. Collectively, it was suggested that XIAP overexpression is associated with delayed blast clearance from the bone marrow or peripheral blood and the resistance of blasts to apoptotic stimuli provided by the chemotherapeutic agents, eventually leading to a worse RFS.
The findings in the present study are basically in line with those by Tamm et al. (15
) in that XIAP overexpression is associated with a worse outcome. However, there are a few important differences between the two studies. First, there was no difference in the level of XIAP expression between FAB M2/M3 and M4/M5 subtype in the present study, while the level of XIAP expression was higher in M4/M5 subtype than in M2/M3 subtype according to the report by Tamm et al. (15
). Second, while Tamm et al. (15
) could detect XIAP expression only in patients with intermediate/unfavorable cytogenetics, we detected XIAP expression even in patients with favorable cytogenetics and there was no difference in the level of XIAP expression between favorable and intermediate/unfavorable cytogenetics. Third, most importantly, the level of XIAP expression was higher in patients who experienced relapse than in those in continuous CR in this study, while Tamm et al. (15
) could not find a significant difference in XIAP expression between the two groups of patients. As a result, they could not find a difference in RFS according to the level of XIAP expression although the high level of XIAP expression was associated with a worse overall survival rate. These differences between the two studies may be partly explained by the difference in methods to measure XIAP expression (quantitative RT-PCR vs. Western blot). In addition, as Tamm et al. (15
) pointed out in their report, selection bias toward samples from patients with high leukocyte counts during cryopreservation of samples and alteration in protein expression by freezing and DMSO might have resulted in different findings from our study.
The IAP family proteins inhibit the apoptosis induced by a variety of stimuli including chemotherapeutic agents, and therefore, their overexpression is expected to be associated with unfavorable clinical features in a variety of malignancies including AML. However, the clinical significance of IAP overexpression in acute leukemia is not completely consistent with what has been expected from previous in vitro studies. For example, IAP overexpression was not always associated with the unfavorable clinical features in acute leukemia (16
). Furthermore, it was recently reported that the high expression of Livin, also a member of IAP family proteins, is an independent favorable prognostic factor in childhood ALL (12
). This suggests that the role of IAP in leukemogenesis or in the maintenance of leukemic cells might be different from what has been previously recognized. However, the findings from this study demonstrated that the clinical significance of XIAP overexpression in childhood AML is consistent with what has been previously recognized from in vitro studies.
In conclusion, this is the first report demonstrating that XIAP overexpression is associated with a worse early response to induction chemotherapy and, eventually, is an independent unfavorable prognostic factor for RFS in childhood AML. Admitting that the number of cases and the follow-up period in this study were limited, we hope this study would prompt other scientists to investigate the implications of XIAP overexpression in childhood AML to confirm our observations in a larger series of patients. Through validation by further studies, XIAP overexpression may be used as an unfavorable prognostic marker in childhood AML.