Inducible expression of AML1-ETO fusion protein endows leukemic cells with susceptibility to extrinsic and intrinsic apoptosis.
AML1-ETO, a leukemia-associated fusion protein generated by the frequently occurred chromosome translocation t(8;21) in acute myeloid leukemia, was shown to exert dichotomous functions in leukemic cells, that is, growth arrest versus differentiation block. By the analysis of oligonucleotide microarray, AML1-ETO was shown to modulate the expressions of an impressive array of pro- and anti-apoptotic genes. Here, we investigate potential effects of the ecdysone inducible AML1-ETO expression on apoptosis of leukemic U937 cell line. We show that AML1-ETO significantly stabilizes death receptor Fas protein and increases proapoptotic Bak in addition to reducing Bcl-2 expression. Accordingly, inducible AML1-ETO expression is followed by apoptosis to a lower degree. Especially, AML1-ETO endows leukemic cells with the susceptibility to anti-Fas agonist antibody, ultraviolet light and camptothecin analog NSC606985-induced apoptosis with increased activation of caspase-3/8. Considering that apoptosis-enhancing effect of AML1-ETO would not be favorable to the leukemogenesis harboring the t(8;21) translocation, it must be overcome to fulfill their leukemogenic potential. Complementary to this prediction is that two AML1-ETO-carrying leukemic cells, Kasumi-1 and SKNO-1, present similar sensitivity to apoptosis induction with AML1-ETO-negative leukemic cells. Therefore, genetic and/or epigenetic screenings of apoptosis-related genes modulated by AML1-ETO deserve to be explored for understanding the mechanisms of AML1-ETO-induced leukemogenesis.
Lu
Y
Y
The Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Xu
Y-B
YB
Yuan
T-T
TT
Song
M-G
MG
Lübbert
M
M
Fliegauf
M
M
Chen
G-Q
GQ
D000911:Antibodies, Monoclonal; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D050676:Core Binding Factor Alpha 2 Subunit / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004441:Ecdysterone / Q000031:analogs & derivatives / Q000494:pharmacology; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015514:Oncogene Proteins, Fusion / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D013997:Time Factors; D014466:Ultraviolet Rays; D019014:fas Receptor
C107844:AML1-ETO fusion protein, human; D000911:Antibodies, Monoclonal; D050676:Core Binding Factor Alpha 2 Subunit; C491901:FAS protein, human; C514334:NSC606985; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D000075142:RUNX1 Translocation Partner 1 Protein; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor; D004441:Ecdysterone; C008999:ponasterone A; D003513:Cycloheximide; D002166:Camptothecin