Sp1/NFκB/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 NFκB/HDAC complex that further represses miR-29b transcription. Upregulated Sp1 then binds NFκB and transactivates KIT. Therefore, activated KIT ultimately induces its own transcription. Our results provide evidence that the mechanisms of Sp1/NFκB/HDAC/ miR-29b-dependent KIT overexpression contribute to leukemia growth and can be successfully targeted by pharmacological disruption of the Sp1/NFκB/HDAC complex or synthetic miR-29b treatment in KIT-driven AML. ► Aberrant KIT activity from mutation or overexpression contributes to leukemogenesis ► KIT activation inhibits miR-29b and unblocks expression of the miR-29b target Sp1 ► Sp1-NFκB recruits HDAC for further miR-29b inhibition, and transactivates KIT ► Therapeutic modulation of miR-29b/Sp1/NFκB/HDAC network overcomes KIT-driven leukemia