Journal
CANCER CELL
Volume 17, Issue 4, Pages 333-347Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2010.03.008
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Funding
- National Cancer Institute (Bethesda, MD) [CA102031, CA077658, CA101140, CA140158, CA114725]
- Harry T. Mangurian Jr. Foundation
- Coleman Leukemia Research Foundation
- Sidney Kimmel Cancer Research Foundation
- Deutsche Krebshilfe
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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 NF kappa B/HDAC complex that further represses miR-29b transcription. Upregulated Sp1 then binds NF kappa B and transactivates KIT. Therefore, activated KIT ultimately induces its own transcription. Our results provide evidence that the mechanisms of Sp1/NF kappa B/HDAC/miR-29b-dependent KIT overexpression contribute to leukemia growth and can be successfully targeted by pharmacological disruption of the Sp1/NF kappa B/HDAC complex or synthetic miR-29b treatment in KIT-driven AML.
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