Inhibitors of histone deacetylase relieve ETO-mediated repression and induce differentiation of AML1-ETO leukemia cells.
The (8;21) translocation, found in 12% of acute myeloid leukemia (AML), creates the chimeric fusion product, AML1-ETO. Previously, we demonstrated that the ETO moiety recruits a transcription repression complex that includes the histone deacetylase (HDAC1) enzyme. Here, we used inhibitors of HDAC1 to study the pathophysiology of AML1-ETO. Both the potent inhibitor, trichostatin (TSA), and the well-known but less specific inhibitor, phenylbutyrate (PB), could partially reverse ETO-mediated transcriptional repression. PB was also able to induce partial differentiation of the AML1-ETO cell line, Kasumi-1. With the intention of developing a clinically useful protocol, we combined PB with a number of other agents that induced differentiation and apoptosis of Kasumi-1 cells. In summary, transcriptional repression mediated by AML1-ETO appears to play a mechanistic role in the t(8;21) AML, and relief of repression using agents such as PB (alone or in combination) may prove to be therapeutically useful.
Wang
J
J
Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892, USA.
Saunthararajah
Y
Y
Redner
R L
RL
Liu
J M
JM
D016475:3T3 Cells; D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics*; D010654:Phenylbutyrates / Q000494:pharmacology; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects*; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009363:Neoplasm Proteins; D010654:Phenylbutyrates; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; C082222:RUNX1T1 protein, human; D011993:Recombinant Fusion Proteins; C493726:Runx1 protein, mouse; D014157:Transcription Factors; C012589:trichostatin A