Age-Associated Difference in Gene Expression of Pediatric Myelo-Monocytic and MLL-Rearranged AML.

Abstract

Acute myelogenous leukemia (AML) is a heterogeneous disease with a variety of genetic alterations including the MLL gene rearrangement. Microarray-based gene expression profiling has been applied to diagnose AML patients and to explore their underlying molecular pathology. In this study, we focused on pediatric myelo-monocytic leukemia and analyzed 40 pediatric AML patients with FAB M4 and M5 subtypes [excluding inv(16) and t(8;21) cases] using Affymetrix HG-U133plus2.0 microarray. Patients consisted of 14 infants (<1 year old) and 26 children (>=1 year old), and 23 patients possessed MLL gene rearrangements. Unsupervised analysis revealed that 10 of the 14 infants display very distinct gene expression and large set of genes were over-expressed among the infants. Among these highly expressed genes, ZFHX1B, ARHGAP26 (GRAF), and FOXO3A (AF6) were included. With the use of these distinctively expressed genes, we were able to divide the 40 pediatric patients into three subgroups: 10 infants with very high expression as Group A, 2 infants and 10 children with medium expression as Group B, and 2 infants and 16 children with low expression as Group C. The average age of Group A was 0.3 year old, Group B was 3.1 years old, and Group C was 6.6 years old. All subgroups included MLL gene rearrangements as well as normal and other complex karyotypes. FAB subtypes were equally distributed among each subgroup. The comparison of the outcomes among the subgroups showed a striking difference where Group C presented extremely poor outcome (3-year EFS 28%). Genes specifically over-expressed among Group C included poor prognostic factors such as WT1 and KIT. In addition, we found that gene expression signature of MLL rearrangement was different among the subgroups as well. For example, EVI1, SOCS2 and MEF2C were up-regulated in MLL-rearranged AML of Group C but not in the others. HOXA9 and HOXA10 were regulated independently of MLL-rearrangement in pediatric myelo-monocytic AML. These results suggest that age is an important factor contributing to the biology of pediatric myelo-monocytic AML and sub-grouping procedures can provide proper stratification so that the poor prognostic subgroup can be distinguished to receive suitable therapy.