| Literature DB >> 20385359 |
Shujun Liu1, Lai-Chu Wu, Jiuxia Pang, Ramasamy Santhanam, Sebastian Schwind, Yue-Zhong Wu, Christopher J Hickey, Jianhua Yu, Heiko Becker, Kati Maharry, Michael D Radmacher, Chenglong Li, Susan P Whitman, Anjali Mishra, Nicole Stauffer, Anna M Eiring, Roger Briesewitz, Robert A Baiocchi, Kenneth K Chan, Peter Paschka, Michael A Caligiuri, John C Byrd, Carlo M Croce, Clara D Bloomfield, Danilo Perrotti, Ramiro Garzon, Guido Marcucci.
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. Copyright 2010 Elsevier Inc. All rights reserved.Entities:
Mesh：
Substances：
Year: 2010 PMID： 20385359 PMCID： PMC2917066 DOI： 10.1016/j.ccr.2010.03.008
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743