title: Accelerated leukemogenesis by truncated CBF beta-SMMHC defective in high-affinity binding with RUNX1.
abstract: 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.
authors.affiliation: Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kamikubo
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
authors.forename: Mark
authors.initials: M
authors.lastname: Wunderlich
authors.forename: Takeshi
authors.initials: T
authors.lastname: Corpora
authors.forename: R Katherine
authors.initials: RK
authors.lastname: Hyde
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Paul
authors.forename: Mondira
authors.initials: M
authors.lastname: Kundu
authors.forename: Lisa
authors.initials: L
authors.lastname: Garrett
authors.forename: Sheila
authors.initials: S
authors.lastname: Compton
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.forename: Linda
authors.initials: L
authors.lastname: Wolff
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ito
authors.forename: John
authors.initials: J
authors.lastname: Bushweller
authors.forename: James C
authors.initials: JC
authors.lastname: Mulloy
authors.forename: P Paul
authors.initials: PP
authors.lastname: Liu
mesh_terms: D000818:Animals; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D050658:Core Binding Factor beta Subunit / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007942:Leukemia, Experimental / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D050658:Core Binding Factor beta Subunit; D015514:Oncogene Proteins, Fusion