Accelerated leukemogenesis by truncated CBFb-SMMHC defective in high-affinity binding with RUNX1

Dominant RUNX1 inhibition has been proposed as a common pathway for CBF-leukemia. CBFb-SMMHC, a fusion protein in human acute myeloid leukemia (AML), dominantly inhibits RUNX1 largely through its RUNX1 high-affinity binding domain (HABD). We generated knock-in mice expressing CBFb-SMMHC with a HABD deletion, CBFb-SMMHCd179-221. These mice developed leukemia highly efficiently, even though hematopoietic defects associated with Runx1-inhibition were partially rescued. To identify changes in gene expression with the deletion of the HABD, we compared the gene expression profile in leukemia samples from mice expressing CBFb-SMMHCd179-221 with those from mice expressing full length CBFb-SMMHC. Spleen cells were isolated from leukemic knock-in mice with full length CBFb-SMMHC at 2 months after ENU treatment and 2 leukemic CBFb-SMMHCd179-221 expressing chimeric mice at 3 weeks after birth. For each genotype, we performed two independent experiments with 4 Affymetrix GeneChip 430 chips.