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

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.

Pubmed ID: 20385359


  • Liu S
  • Wu LC
  • Pang J
  • Santhanam R
  • Schwind S
  • Wu YZ
  • Hickey CJ
  • Yu J
  • Becker H
  • Maharry K
  • Radmacher MD
  • Li C
  • Whitman SP
  • Mishra A
  • Stauffer N
  • Eiring AM
  • Briesewitz R
  • Baiocchi RA
  • Chan KK
  • Paschka P
  • Caligiuri MA
  • Byrd JC
  • Croce CM
  • Bloomfield CD
  • Perrotti D
  • Garzon R
  • Marcucci G


Cancer cell

Publication Data

April 13, 2010

Associated Grants

  • Agency: NCI NIH HHS, Id: CA077658
  • Agency: NCI NIH HHS, Id: CA101140
  • Agency: NCI NIH HHS, Id: CA102031
  • Agency: NCI NIH HHS, Id: CA114725
  • Agency: NCI NIH HHS, Id: CA140158
  • Agency: NCI NIH HHS, Id: P50 CA140158
  • Agency: NCI NIH HHS, Id: R01 CA095512
  • Agency: NCI NIH HHS, Id: R01 CA102031
  • Agency: NCI NIH HHS, Id: R01 CA102031-07
  • Agency: NCRR NIH HHS, Id: UL1 RR025755

Mesh Terms

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