Association of time to leukemia (TTL) in NOD/SCID mice with expression of apoptosis regulators in pediatric ALL

10042 Background: Acute lymphoblastic leukemia (ALL) is the most frequent malignant disease in childhood. Although advances in therapy have led to improved long term survival, relapse remains a major challenge. In a recent study we transplanted pediatric leukemia samples from newly diagnosed BCP-ALL patients into NOD/SCID mice. Time to leukemia (TTL) was analyzed for each patient sample as time from transplant to overt leukemia in the recipients. Patients whose leukemia cells engrafted rapidly showed a clearly inferior relapse free survival in contrast to patient samples with prolonged in vivo growth. Multivariate analysis showed an almost 45- fold increased risk for relapse in patients with short TTL. Methods: Gene expression profiles of ALL samples (N = 14) with short versus long TTL in the xenograft model were analyzed using a human whole genome array (Affymetrix U133 Plus 2.0) correlating gene expression values (relative expression) to the time from transplant to manifestation of leukemia in the NOD/SCID mice (TTL, in weeks) by quantitative traits analysis (QTA). Results: Among 5 genes significantly correlated (Spearman correlation, P < .0001) XIAP-associated factor 1 (XAF1) was found to be up-regulated in patients with long TTL. XAF1 abrogates the inhibitory effect of XIAP on caspase-3 thereby sensitizing for apoptosis. In accordance to this caspase-3 activation was also found to be up-regulated in patients with long TTL. Patient samples exhibiting a short time to overt leukemia in the xenotransplant model associated with poor relapse free survival showed down-regulated XAF1 and impaired caspase-3 activation leading to decreased apoptosis of the leukemia cells. Conclusions: Taken together, we used a novel approach directly correlating gene expression values to time from transplant to overt leukemia (TTL) identifying the apoptosis regulator XAF1 to be associated with poor outcome of patients. Small XIAP-inhibiting molecules can be used to substitute the lacking inhibitory effect of down-regulated XAF1 in these poor responding pediatric ALL patients. No significant financial relationships to disclose.