Aberrant Transcriptional Regulation of the MLL Fusion Partner EEN Gene by AML1-ETO and Its Implication in Leukemogenesis.

EEN (extra eleven nineteen) gene located on chromosome 19p13 was cloned as a fusion with MLL from an acute myeloid leukemia (AML) patient with translocation t(11;19)(q23;p13). In this study, we characterized the genomic structure of EEN gene including its 5′ regulatory region and transcription start site (TSS). We found that Sp1 could bind to the GC-stretch of EEN promoter and was critical for the normal EEN expression, while the leukemia associated fusion protein AML1-ETO could aberrantly transactivate EEN gene through an AML1 binding site. Of note, overexpressed EEN showed oncogenic properties, such as transforming potential in NIH3T3 cells, stimulating cell proliferation and increasing the activity of transcriptional factor AP-1. Retroviral transduction of EEN increased self-renewal and proliferation of murine hematopoietic progenitor cells. Moreover, Kasumi-1 and HL60 cell growth was inhibited with down regulation of EEN by RNAi. These findings demonstrate that EEN might be a common target in two major types of AML associated with MLL or AML1 translocations, and over-expression of EEN may play an essential role in leukemogenesis.