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 RIS Download
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