title: Heterodimerization of AML1/ETO with CBFβ is required for leukemogenesis but not for myeloproliferation.
abstract: The AML1/Runx1 transcription factor and its heterodimerization partner CBFβ are essential regulators of myeloid differentiation. The chromosomal translocation t(8;21), fusing the DNA binding domain of AML1 to the corepressor eight-twenty-one (ETO), is frequently associated with acute myeloid leukemia and generates the AML1/ETO (AE) fusion protein. AE represses target genes usually activated by AML1 and also affects the endogenous repressive function of ETO at Notch target genes. In order to analyze the contribution of CBFβ in AE-mediated leukemogenesis and deregulation of Notch target genes, we introduced two point mutations in a leukemia-initiating version of AE in mice, called AE9a, that disrupt the AML1/CBFβ interaction (AE9aNT). We report that the AE9a/CBFβ interaction is not required for the AE9a-mediated aberrant expression of AML1 target genes, while upregulation/derepression of Notch target genes does require the interaction with CBFβ. Using retroviral transduction to express AE9a in murine adult bone marrow-derived hematopoietic progenitors, we observed that both AE9a and AE9aNT lead to increased myeloproliferation in vivo. However, both development of leukemia and long-term replating capacity are only observed with AE9a but not with AE9aNT. Thus, deregulation of both AML1 and Notch target genes is required for the development of AE9a-driven leukemia.
authors.affiliation: University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine I, University of Ulm, Ulm, Germany.
authors.forename: V N
authors.initials: VN
authors.lastname: Thiel
authors.affiliation: Institute of Biochemistry, University of Giessen, Giessen, Germany.
authors.forename: B D
authors.initials: BD
authors.lastname: Giaimo
authors.affiliation: University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine I, University of Ulm, Ulm, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Schwarz
authors.affiliation: Institute of Molecular Medicine, University of Ulm, Ulm, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Soller
authors.affiliation: Institute of Molecular Medicine, University of Ulm, Ulm, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Vas
authors.affiliation: Institute for Genetics, University of Giessen, Giessen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Bartkuhn
authors.affiliation: University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: T J
authors.initials: TJ
authors.lastname: Blätte
authors.affiliation: University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Döhner
authors.affiliation: University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Institute of Biochemistry, University of Giessen, Giessen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Borggrefe
authors.affiliation: Institute of Molecular Medicine, University of Ulm, Ulm, Germany.|Division of Experimental Hematology and Cancer Biology, CCHMC, Cincinnati, OH, USA.
authors.forename: H
authors.initials: H
authors.lastname: Geiger
authors.affiliation: University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine I, University of Ulm, Ulm, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Oswald
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D050658:Core Binding Factor beta Subunit / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D000075142:RUNX1 Translocation Partner 1 Protein / Q000378:metabolism*
chemical_list: C107844:AML1-ETO fusion protein, human; C493692:CBFB protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D050658:Core Binding Factor beta Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human