Specific protein redirection as a transcriptional therapy approach for t(8;21) leukemia.
Important progress has been achieved in the knowledge about the pathogenesis of cancer. However, despite these advances, the therapeutic strategies are still limited. Leukemias are often characterized by specific balanced translocations, with the t(8;21) balanced translocation being the most frequent chromosomal aberration in acute myeloid leukemia (AML). This translocation produces the AML1-ETO fusion protein, which binds to AML1 target promoter sequences. Transcriptional repression of AML1-dependent genes by AML1-ETO and associated corepressors represents the pathogenetic mechanisms of t(8;21). Here, we show that targeting of AML1-ETO to essential, MYB-dependent gene promoters induces t(8;21)-restricted cell death. We constructed a chimeric protein that contained the MYB DNA-binding domain and the AML1-binding domain of myeloid Elf-1-like factor (MEF). This protein associated with AML1-ETO and directed the complex to MYB-responsive promoters in vitro and in vivo. In the presence of AML1-ETO, the chimeric protein repressed the activity of MYB-responsive promoters, rapidly induced apoptosis, and specifically inhibited colony growth. All these effects occurred only in AML1-ETO-positive cells, whereas no adverse effects were observed in cells not expressing AML1-ETO. Taken together, this study demonstrates that redirection of oncogenic proteins can be used as a strategy to dramatically influence their cellular effects, with the ultimate goal to design highly specific therapies for cancer.
Steffen
Björn
B
Department of Medicine, Hematology/Oncology, University of Münster, 48129 Münster, Germany.
Serve
Hubert
H
Berdel
Wolfgang E
WE
Agrawal
Shuchi
S
Linggi
Bryan
B
Büchner
Thomas
T
Hiebert
Scott W
SW
Müller-Tidow
Carsten
C
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001665:Binding Sites; D019556:COS Cells; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics / Q000648:ultrastructure*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics / Q000648:ultrastructure*; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D020570:Genes, myb; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D046911:Macromolecular Substances; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D015513:Oncogene Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit; D020598:Proto-Oncogene Proteins c-myb / Q000737:chemistry / Q000502:physiology; D000075142:RUNX1 Translocation Partner 1 Protein; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology*; D013379:Substrate Specificity; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; C111931:ELF4 protein, human; C491779:Elf4 protein, mouse; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D020598:Proto-Oncogene Proteins c-myb; D000075142:RUNX1 Translocation Partner 1 Protein; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D019009:Proto-Oncogene Proteins c-kit