Aberrant transcriptional regulation of the MLL fusion partner EEN by AML1-ETO and its implication in leukemogenesis.
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.
Ma
Li-Heng
LH
State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital affiliated to School of Medicine, Shanghai Jiao Tong University, 197 Ruijin Road II, Shanghai 200025, China.
Liu
Han
H
Xiong
Hui
H
Chen
Bing
B
Zhang
Xiao-Wei
XW
Wang
Yue-Ying
YY
Le
Huang-Ying
HY
Huang
Qiu-Hua
QH
Zhang
Qing-Hua
QH
Li
Bo-Liang
BL
Chen
Zhu
Z
Chen
Sai-Juan
SJ
D000208:Acute Disease; D000818:Animals; D002471:Cell Transformation, Neoplastic; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000235:genetics*; D015674:Mammary Neoplasms, Animal; D051379:Mice; D008819:Mice, Nude; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D000075142:RUNX1 Translocation Partner 1 Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012680:Sensitivity and Specificity; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*; D020298:U937 Cells
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D047908:Intracellular Signaling Peptides and Proteins; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; C105159:SH3GL1 protein, human; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein