Sp1/NFkappaB/HDAC/miR-29b regulatory network in KIT-driven myeloid leukemia

Cancer Cell. 2010 Apr 13;17(4):333-47. doi: 10.1016/j.ccr.2010.03.008.


The biologic and clinical significance of KIT overexpression that associates with KIT gain-of-function mutations occurring in subsets of acute myeloid leukemia (AML) (i.e., core binding factor AML) is unknown. Here, we show that KIT mutations lead to MYC-dependent miR-29b repression and increased levels of the miR-29b target Sp1 in KIT-driven leukemia. Sp1 enhances its own expression by participating in a NFkappaB/HDAC complex that further represses miR-29b transcription. Upregulated Sp1 then binds NFkappaB and transactivates KIT. Therefore, activated KIT ultimately induces its own transcription. Our results provide evidence that the mechanisms of Sp1/NFkappaB/HDAC/miR-29b-dependent KIT overexpression contribute to leukemia growth and can be successfully targeted by pharmacological disruption of the Sp1/NFkappaB/HDAC complex or synthetic miR-29b treatment in KIT-driven AML.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Chromosomes, Human, Pair 7 / genetics
  • Gene Expression Regulation, Neoplastic
  • Genetic Vectors
  • Histone Deacetylases / physiology*
  • Homeostasis
  • Humans
  • Immunoglobulins / physiology*
  • Leukemia, Myeloid / genetics*
  • Leukemia, Myeloid / physiopathology
  • MicroRNAs / physiology*
  • NF-kappa B / physiology*
  • Proto-Oncogene Proteins c-kit / genetics*
  • Transcription, Genetic


  • Immunoglobulins
  • MIRN29a microRNA, human
  • MicroRNAs
  • NF-kappa B
  • SP1 antigen
  • Proto-Oncogene Proteins c-kit
  • Histone Deacetylases