Author/Authors :
Kamikubo، نويسنده , , Yasuhiko and Zhao، نويسنده , , Ling and Wunderlich، نويسنده , , Mark and Corpora، نويسنده , , Takeshi and Hyde، نويسنده , , R. Katherine and Paul، نويسنده , , Thomas A. and Kundu، نويسنده , , Mondira and Garrett، نويسنده , , Lisa and Compton، نويسنده , , Sheila and Huang، نويسنده , , Gang and Wolff، نويسنده , , Linda and Ito، نويسنده , , Yoshiaki and Bushweller، نويسنده , , John and Mulloy، نويسنده , , James C. and Liu، نويسنده , , P. Paul، نويسنده ,
Abstract :
Summary
nt RUNX1 inhibition has been proposed as a common pathway for CBF leukemia. CBFβ-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 CBFβ-SMMHC fusion in AML patients lacks HABD. Here, we report that the type I CBFβ-SMMHC protein binds RUNX1 inefficiently. Knockin mice expressing CBFβ-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 CBFβ-SMMHC.
