Aberrant transcriptional regulation of the MLL fusion partner EEN by AML1-ETO and its implication in leukemogenesis

Author:

Ma Li-Heng12,Liu Han1,Xiong Hui3,Chen Bing1,Zhang Xiao-Wei1,Wang Yue-Ying1,Le Huang-Ying1,Huang Qiu-Hua1,Zhang Qing-Hua1,Li Bo-Liang4,Chen Zhu12,Chen Sai-Juan12

Affiliation:

1. State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital affiliated to School of Medicine, Shanghai Jiao Tong University (SJTU), Shanghai, China;

2. Shanghai Center for Systems Biomedicine, SJTU, Shanghai, China;

3. Shanghai Laboratory of Disease and Health Genomics, Chinese National Human Genome Center at Shanghai;

4. Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

Abstract

Abstract The EEN (extra eleven nineteen) gene, located on chromosome 19p13, was cloned as a fusion with MLL from a patient with acute myeloid leukemia (AML) with translocation t(11;19)(q23;p13). In this study, we characterized the genomic structure of the EEN gene, including its 5′ regulatory region and transcription start site (TSS). We found that Sp1 could bind to the guanine-cytosine (GC)–stretch of the EEN promoter and was critical for the normal EEN expression, whereas the leukemia-associated fusion protein AML1-ETO could aberrantly transactivate the 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 2 major types of AML associated with MLL or AML1 translocations, and overexpression of EEN may play an essential role in leukemogenesis.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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