The AML1/Evi-1 fusion protein in the t(3;21) translocation exhibits transforming activity on Rat1 fibroblasts with dependence on the Evi-1 sequence.
The t(3;21) (q26;q22) chromosomal translocation associated with blastic crisis of chronic myelogenous leukemia (CML) results in the formation of a chimeric protein fusing the amino-terminal DNA-binding domain encoded by the AML1 gene to the carboxyl-terminal-encoding portion of the Evi-1 gene. In order to evaluate transforming activity of this protein, AML1/Evi-1 was introduced into Rat1 fibroblasts. Cells expressing the fusion product formed macroscopic colonies in soft agar, indicating that AML1/Evi-1 is a transforming gene. It was also demonstrated that introduction of AML1/Evi-1 into the Rat1 clones harboring BCR/ABL also conferred enhanced capacity for anchorage independent growth. Analyses of deletion mutants of AML1/Evi-1 revealed that removal of the second zinc finger domain within the Evi-1 sequence totally abrogated the ability of AML1/Evi-1 to transform Rat1 cells. We showed that the transforming effect is correlated with the AP-1 activation induced by AML1/Evi-1. Furthermore, we demonstrated that c-jun is transcriptionally activated in Rat1 cells transformed by AML1/Evi-1, suggesting that c-jun expression is under control of AML1/Evi-1. These results indicate that the oncogenic effect of the t(3;21) translocation is caused by the generation of a chimeric transcriptional factor and that AML1/Evi-1 could perform a pivotal role in leukemic progression of CML.
Kurokawa
M
M
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Ogawa
S
S
Tanaka
T
T
Mitani
K
K
Yazaki
Y
Y
Witte
O N
ON
Hirai
H
H
D016475:3T3 Cells; D000818:Animals; D002471:Cell Transformation, Neoplastic; D002891:Chromosomes, Human, Pair 21; D002893:Chromosomes, Human, Pair 3; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000502:physiology*; D016758:Genes, jun; D006801:Humans; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D009363:Neoplasm Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D011519:Proto-Oncogenes; D011817:Rabbits; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology*; D013329:Structure-Activity Relationship; D018808:Transcription Factor AP-1 / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D014178:Translocation, Genetic; D016335:Zinc Fingers
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; C499305:Mecom protein, mouse; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D011993:Recombinant Fusion Proteins; C493726:Runx1 protein, mouse; C493727:Runx1 protein, rat; D018808:Transcription Factor AP-1; D014157:Transcription Factors