Key Points

SMMHCC95 knock-in mice have normal hematopoiesis. Heterozygous CBF-SMMHCC95 knock-in mice do not develop leukemia. 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-SMMHCC95). Embryos with a single copy of CBF-SMMHCC95 were viable and showed no defects in hematopoiesis, whereas embryos homozygous for the CBF-SMMHCC95 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-SMMHCC95 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. (Blood. 2013;121(4):638-642