EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia

Abstract

Overexpression of the ecotropic virus integration-1 (EVI1) gene (EVI1 þ ), localized at chromosome 3q26, is associated with adverse outcome in adult acute myeloid leukemia (AML). In pediatric AML, 3q26 abnormalities are rare, and the role of EVI1 is unknown. We studied 228 pediatric AML samples for EVI1 þ using gene expression profiling and RQ-PCR. EVI1 þ was found in 20/213 (9%) of children with de novo AML, and in 4/8 with secondary AML. It was predominantly found in MLLrearranged AML (13/47), monosomy 7 (2/3), or FAB M6/7 (6/10), and mutually exclusive with core-binding factor AML, t(15;17), and NPM1 mutations. Fluorescent in situ hybridization (FISH) was performed to detect cryptic 3q26 abnormalities. However, none of the EVI1 þ patients harbored structural 3q26 alterations. Although significant differences in 4 years pEFS for EVI1 þ and EVI1À pediatric AML were observed (28%±11 vs 44%±4, P ¼ 0.04), multivariate analysis did not identify EVI1 þ as an independent prognostic factor. We conclude that EVI1 þ can be found in B10% of pediatric AML. Although EVI1 þ was not an independent prognostic factor, it was predominantly found in subtypes of pediatric AML that are related with an intermediate to unfavorable prognosis. Further research should explain the role of EVI1 þ in disease biology in these cases. Remarkably, no 3q26 abnormalities were identified in EVI1 þ pediatric AML.

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

“…101,102 We confirmed this in pediatric AML, where overexpression of EVI1 is mainly associated with a subset of MLL-rearranged AML. 103 All cases with a t(6;11)(q27;q23), that carry a very poor outcome, showed overexpression of EVI1, consistent with adult t(6;11)(q27;q23) cases. This suggests a role for EVI1 in leukemogenesis in these specific cases.…”

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

“…In pediatric AML, it was predominantly found in groups with a poor outcome, including FAB-M7 and t(6;11)(q27;q23). 27 Therefore, high BRE expression seems to be part of a favorable signature in MLL-rearranged AML.…”

“…[22][23][24][25][26] Overexpression of EVI1 was previously established by gene expression profiling and real-time quantitative (RQ)-PCR. 27 Microarray-based gene expression profiling Integrity of total RNA was checked using the Agilent 2100 Bioanalyzer (Agilent, Santa Clara, CA, USA). Complementary DNA and biotinylated complementary RNA were synthesized, hybridized and processed on the Affymetrix Human Genome U133 Plus 2.0 Array (Affymetrix, Santa Clara, CA, USA) according to the manufacturer's guidelines.…”

EVI1 is critical for the pathogenesis of a subset of MLL-AF9–rearranged AMLs

“…In addition, in pediatric AMLs, in 27% of MLL rearranged cases, EVI1 overexpression was detected. 22 In a knockin MLL-AF9 mouse model mimicking human AML development, high Evi1 expression was detected in preleukemic stem and progenitor cells compared with corresponding wild-type cells. 23 Importantly, among the various MLL-AF9 hematopoietic stem and progenitor cells, a direct correlation between Evi1 expression and the level of transformation was observed, where the Lin Ϫ /Sca1 ϩ /c-Kit ϩ (LSK) cells exhibiting highest Evi1 expression induced leukemias with the highest efficiency in recipients that received transplants.…”