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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


  • Kamikubo Y
  • Zhao L
  • Wunderlich M
  • Corpora T
  • Hyde RK
  • Paul TA
  • Kundu M
  • Garrett L
  • Compton S
  • Huang G
  • Wolff L
  • Ito Y
  • Bushweller J
  • Mulloy JC
  • Liu PP


Cancer cell

Publication Data

May 18, 2010

Associated Grants

  • Agency: NCI NIH HHS, Id: CA118319
  • Agency: NCRR NIH HHS, Id: M01 RR 08084
  • Agency: Intramural NIH HHS, Id: Z01 HG000030-13
  • Agency: Intramural NIH HHS, Id: Z01 HG000030-14
  • Agency: Intramural NIH HHS, Id: Z99 HG999999
  • Agency: Intramural NIH HHS, Id: ZIA HG000030-15

Mesh Terms

  • Animals
  • Core Binding Factor Alpha 2 Subunit
  • Core Binding Factor beta Subunit
  • Humans
  • Leukemia, Experimental
  • Mice
  • Mice, Transgenic
  • Oncogene Proteins, Fusion
  • Phosphorylation
  • Protein Binding