title: Deletion of an AML1-ETO C-terminal NcoR/SMRT-interacting region strongly induces leukemia development.
abstract: Normal blood-cell differentiation is controlled by regulated gene expression and signal transduction. Transcription deregulation due to chromosomal translocation is a common theme in hematopoietic neoplasms. AML1-ETO, which is a fusion protein generated by the 8;21 translocation that is commonly associated with the development of acute myeloid leukemia, fuses the AML1 runx family DNA-binding transcription factor to the ETO corepressor that associates with histone deacetylase complexes. Analyses have demonstrated that AML1-ETO blocks AML1 function and requires additional mutagenic events to promote leukemia. Here, we report that the loss of the molecular events of AML1-ETO C-terminal NCoR/SMRT-interacting domain transforms AML1-ETO into a potent leukemogenic protein. Contrary to full-length AML1-ETO, the truncated form promotes in vitro growth and does not obstruct the cell-cycle machinery. These observations suggest a previously uncharacterized mechanism of tumorigenesis, in which secondary mutation(s) in molecular events disrupting the function of a domain of the oncogene promote the development of malignancy.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.forename: Sebastien A
authors.initials: SA
authors.lastname: Burel
authors.forename: Luke F
authors.initials: LF
authors.lastname: Peterson
authors.forename: Eiki
authors.initials: E
authors.lastname: Kanbe
authors.forename: Hiromi
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Anita
authors.initials: A
authors.lastname: Boyapati
authors.forename: Robert
authors.initials: R
authors.lastname: Hines
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D022423:Myeloid Cells / Q000166:cytology; D056985:Nuclear Receptor Co-Repressor 2; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D011485:Protein Binding; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins / Q000378:metabolism*; D017384:Sequence Deletion; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D014161:Transduction, Genetic
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; C539130:NCOR2 protein, human; C539131:Ncor2 protein, mouse; D056985:Nuclear Receptor Co-Repressor 2; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins; D014157:Transcription Factors