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

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

Author information

1
Division of Hematology-Oncology, The Ohio State University, Columbus, OH 43210, USA. shujun.liu@osumc.edu

Abstract

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.

PMID:
20385359
PMCID:
PMC2917066
DOI:
10.1016/j.ccr.2010.03.008
[Indexed for MEDLINE]
Free PMC Article

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