Accelerated Leukemogenesis by Truncated CBFβ-SMMHC Defective in High-Affinity Binding with RUNX1

Yasuhiko Kamikubo, Ling Zhao, Mark Wunderlich, Takeshi Corpora, R. Katherine Hyde, Thomas A. Paul, Mondira Kundu, Lisa Garrett, Sheila Compton, Gang Huang, Linda Wolff, Yoshiaki Ito, John Bushweller, James C. Mulloy, P. Paul Liu

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Dominant 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.

Original languageEnglish (US)
Pages (from-to)455-468
Number of pages14
JournalCancer Cell
Volume17
Issue number5
DOIs
StatePublished - May 18 2010

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Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Kamikubo, Y., Zhao, L., Wunderlich, M., Corpora, T., Hyde, R. K., Paul, T. A., Kundu, M., Garrett, L., Compton, S., Huang, G., Wolff, L., Ito, Y., Bushweller, J., Mulloy, J. C., & Liu, P. P. (2010). Accelerated Leukemogenesis by Truncated CBFβ-SMMHC Defective in High-Affinity Binding with RUNX1. Cancer Cell, 17(5), 455-468. https://doi.org/10.1016/j.ccr.2010.03.022