High BRE expression in pediatric MLL-rearranged AML is associated with favorable outcome

Abstract

Translocations involving the mixed lineage leukemia (MLL) gene, localized at 11q23, frequently occur in pediatric acute myeloid leukemia (AML). We recently reported differences in prognosis between the different translocation partners, suggesting differences in biological background. To unravel the latter, we used microarrays to generate gene expression profiles of 245 pediatric AML cases, including 53 MLL-rearranged cases. Thereby, we identified a specific gene expression signature for t(9;11)(p22;q23), and identified BRE (brain and reproductive organ expressed) to be discriminative for t(9;11)(p22;q23) (P<0.001) when compared with other MLL subtypes. Patients with high BRE expression showed a significantly better 3-year relapse-free survival (pRFS) (80±13 vs 30±10%, P=0.02) within MLL-rearranged AML cases. Moreover, multivariate analysis identified high BRE expression as an independent favorable prognostic factor within pediatric AML for RFS (HR=0.2, P=0.04). No significant differences were identified for 3-year event-free survival or for 3-year overall survival. Forced expression of BRE did not result in altered cell proliferation, apoptosis or drug sensitivity, which could explain the favorable outcome. In conclusion, overexpression of the BRE gene is predominantly found in MLL-rearranged AML with t(9;11)(p22;q23). Although further investigation for the role of BRE in leukemogenesis and outcome is warranted, high BRE expression is an independent prognostic factor for pRFS in pediatric AML.