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

ABSTRACT

The C-terminus of CBFß-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 CBFß-SMMHC. To test the role of the fusion protein's C-terminus in vivo, we generated knock-in mice expressing a C-terminally truncated CBFß-SMMHC (CBFß-SMMHCΔC95). Embryos with a single copy of CBFß-SMMHCΔC95 were viable and showed no defects in hematopoiesis, whereas embryos homozygous for the CBFß-SMMHCΔC95 allele had hematopoietic defects and died in mid-gestation, similar to embryos with a single-copy of the full-length CBFß-SMMHC. Importantly, unlike mice expressing full-length CBFß-SMMHC, none of the mice expressing CBFß-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 CBFß-SMMHC's C-terminus is essential to induce embryonic hematopoietic defects and leukemogenesis.