Author/Authors :
Liu، نويسنده , , Shujun and Wu، نويسنده , , Lai-Chu and Pang، نويسنده , , Jiuxia and Santhanam، نويسنده , , Ramasamy and Schwind، نويسنده , , Sebastian and Wu، نويسنده , , Yue-Zhong and Hickey، نويسنده , , Christopher J. and Yu، نويسنده , , Jianhua and Becker، نويسنده , , Heiko and Maharry، نويسنده , , Kati and Radmacher، نويسنده , , Michael D. and Li، نويسنده , , Chenglong and Whitman، نويسنده , , Susan P. and Mishra، نويسنده , , Anjali and Stauffer، نويسنده , , Nicole and Eiring، نويسنده , , Anna M. and Briesewitz، نويسنده , , Roger and Baiocchi، نويسنده , , Robert A. and Chan، نويسنده , , Kenneth K. and Paschka، نويسنده , , Peter and Caligiuri، نويسنده , , Michael A. and Byrd، نويسنده , , John C. and Croce، نويسنده , , Carlo M. and Bloomfield، نويسنده , , Clara D. and Perrotti، نويسنده , , Danilo and Garzon، نويسنده , , Ramiro and Marcucci، نويسنده , , Guido، نويسنده ,
Abstract :
Summary
ologic 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.
