Dichotomy of AML1-ETO functions: growth arrest versus block of differentiation.
The fusion gene AML1-ETO is the product of t(8;21)(q22;q22), one of the most common chromosomal translocations associated with acute myeloid leukemia. To investigate the impact of AML1-ETO on hematopoiesis, tetracycline-inducible AML1-ETO-expressing cell lines were generated using myeloid cells. AML1-ETO is tightly and strongly induced upon tetracycline withdrawal. The proliferation of AML1-ETO(+) cells was markedly reduced, and most of the cells eventually underwent apoptosis. RNase protection assays revealed that the amount of Bcl-2 mRNA was decreased after AML1-ETO induction. Enforced expression of Bcl-2 was able to significantly delay, but not completely overcome, AML1-ETO-induced apoptosis. Prior to the onset of apoptosis, we also studied the ability of AML1-ETO to modulate differentiation. AML1-ETO expression altered granulocytic differentiation of U937T-A/E cells. More significantly, this change of differentiation was associated with the down-regulation of CCAAT/enhancer binding protein alpha (C/EBPalpha), a key regulator of granulocytic differentiation. These observations suggest a dichotomy in the functions of AML1-ETO: (i) reduction of granulocytic differentiation correlated with decreased expression of C/EBPalpha and (ii) growth arrest leading to apoptosis with decreased expression of CDK4, c-myc, and Bcl-2. We predict that the preleukemic AML1-ETO(+) cells must overcome AML1-ETO-induced growth arrest and apoptosis prior to fulfilling their leukemogenic potential.
Burel
S A
SA
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
Harakawa
N
N
Zhou
L
L
Pabst
T
T
Tenen
D G
DG
Zhang
D E
DE
D017209:Apoptosis / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000502:physiology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000502:physiology*; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors