The C-terminus of CBF?-SMMHC is required to induce embryonic hematopoietic defects and leukemogenesis.

ABSTRACT: The C-terminus of CBF?-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 CBF?-SMMHC. To test the role of the fusion protein's C-terminus in vivo, we generated knock-in mice expressing a C-terminally truncated CBF?-SMMHC (CBF?-SMMHC?C95). Embryos with a single copy of CBF?-SMMHC?C95 were viable and showed no defects in hematopoiesis, whereas embryos homozygous for the CBF?-SMMHC?C95 allele had hematopoietic defects and died in mid-gestation, similar to embryos with a single-copy of the full-length CBF?-SMMHC. Importantly, unlike mice expressing full-length CBF?-SMMHC, none of the mice expressing CBF?-SMMHC?C95 developed leukemia, even after treatment with a mutagen, although some of the older mice developed a nontransplantable myeloproliferative disease. Our data indicate that the CBF?-SMMHC's C-terminus is essential to induce embryonic hematopoietic defects and leukemogenesis.

SUBMITTER: Kamikubo Y 

PROVIDER: S-EPMC3557645 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature