Accelerated leukemogenesis by truncated CBF beta-SMMHC defective in high-affinity binding with RUNX1.
Dominant RUNX1 inhibition has been proposed as a common pathway for CBF leukemia. CBF beta-SMMHC, a fusion protein in human acute myeloid leukemia (AML), dominantly inhibits RUNX1 largely through its RUNX1 high-affinity binding domain (HABD). However, the type I CBF beta-SMMHC fusion in AML patients lacks HABD. Here, we report that the type I CBF beta-SMMHC protein binds RUNX1 inefficiently. Knockin mice expressing CBF beta-SMMHC with a HABD deletion developed leukemia quickly, even though hematopoietic defects associated with Runx1-inhibition were partially rescued. A larger pool of leukemia-initiating cells, increased MN1 expression, and retention of RUNX1 phosphorylation are potential mechanisms for accelerated leukemia development in these mice. Our data suggest that RUNX1 dominant inhibition may not be a critical step for leukemogenesis by CBF beta-SMMHC.
Pubmed ID: 20478528 RIS Download
Animals | Core Binding Factor Alpha 2 Subunit | Core Binding Factor beta Subunit | Humans | Leukemia, Experimental | Mice | Mice, Transgenic | Oncogene Proteins, Fusion | Phosphorylation | Protein Binding