title: The C-terminus of CBFβ-SMMHC is required to induce embryonic hematopoietic defects and leukemogenesis.
abstract: The C-terminus of CBFβ-SMMHC, the fusion protein produced by a chromosome 16 inversion in acute myeloid leukemia subtype M4Eo, contains domains for self-multimerization and transcriptional repression, both of which have been proposed to be important for leukemogenesis by CBFβ-SMMHC. To test the role of the fusion protein's C-terminus in vivo, we generated knock-in mice expressing a C-terminally truncated CBFβ-SMMHC (CBFβ-SMMHCΔC95). Embryos with a single copy of CBFβ-SMMHCΔC95 were viable and showed no defects in hematopoiesis, whereas embryos homozygous for the CBFβ-SMMHCΔC95 allele had hematopoietic defects and died in mid-gestation, similar to embryos with a single-copy of the full-length CBFβ-SMMHC. Importantly, unlike mice expressing full-length CBFβ-SMMHC, none of the mice expressing CBFβ-SMMHCΔC95 developed leukemia, even after treatment with a mutagen, although some of the older mice developed a nontransplantable myeloproliferative disease. Our data indicate that the CBFβ-SMMHC's C-terminus is essential to induce embryonic hematopoietic defects and leukemogenesis.
authors.affiliation: Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. pliu@mail.nih.gov
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kamikubo
authors.forename: R Katherine
authors.initials: RK
authors.lastname: Hyde
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
authors.forename: Lemlem
authors.initials: L
authors.lastname: Alemu
authors.forename: Cecilia
authors.initials: C
authors.lastname: Rivas
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Garrett
authors.forename: P Paul
authors.initials: PP
authors.lastname: Liu
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D015973:Gene Expression Regulation, Leukemic; D055879:Gene Knock-In Techniques; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C095514:CBFbeta-MYH11 fusion protein; D015514:Oncogene Proteins, Fusion