title: Attenuation of AML1-ETO cellular dysregulation correlates with increased leukemogenic potential.
abstract: AML1-ETO (RUNX1-ETO) fusion proteins are generated by the 8;21 translocation, commonly found in acute myeloid leukemia, which fuses the AML1 (RUNX1) and ETO (MTG8, RUNX1T1) genes. Previous studies have shown that AML1-ETO interferes with AML1 function but requires additional cooperating mutations to induce leukemia development. In mouse models, AML1-ETO forms lacking the C-terminus have been shown to have greatly enhanced leukemogenic potential. Here, we investigate the role of 2 AML1-ETO C-terminal-interacting proteins, N-CoR, a transcriptional corepressor, and SON, a splicing/transcription factor required for cell cycle progression, in AML1-ETO-induced leukemia development. AML1-ETO-W692A loses N-CoR binding at NHR4, displays attenuated transcriptional repression ability and decreased cellular dysregulation, and promotes leukemia in vivo. These results support the importance of the degree of dysregulation by AML1-ETO in cellular transformation and demonstrate that AML1-ETO-W692A can be used as an effective experimental model for determining which factors compromise the leukemogenic potential of AML1-ETO.
authors: Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.
authors: Russell C
authors: RC
authors: DeKelver
authors: Ming
authors: M
authors: Yan
authors: Eun-Young
authors: EY
authors: Ahn
authors: Wei-Jong
authors: WJ
authors: Shia
authors: Nancy A
authors: NA
authors: Speck
authors: Dong-Er
authors: DE
authors: Zhang
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D056971:Nuclear Receptor Co-Repressor 1; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein