Sp1/NFκB/HDAC/miR-29b Regulatory Network in KIT-Driven Myeloid Leukemia

Shujun Liu, 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 PaschkaMichael A. Caligiuri, John C. Byrd, Carlo M. Croce, Clara D. Bloomfield, Danilo Perrotti, Ramiro Garzon, Guido Marcucci

Research output: Contribution to journalArticlepeer-review

204 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)333-347
Number of pages15
JournalCancer Cell
Volume17
Issue number4
DOIs
StatePublished - Apr 13 2010

Bibliographical note

Funding Information:
Supported in part by National Cancer Institute (Bethesda, MD) grants CA102031, CA077658, CA101140, CA140158, CA114725, the Harry T. Mangurian Jr. Foundation Leukemia Research Fund, the Coleman Leukemia Research Foundation, the Sidney Kimmel Cancer Research Foundation, and the Deutsche Krebshilfe (Dr. Mildred Scheel Foundation for Cancer Research). We thank Dr. Clara Nervi for providing the SKNO-1 cell line, Drs. Kathryn G. Roberts and Nicole Verrills for providing FDC-P1 cell lines, and J. Kearney-Bryan and Drs. R. Klisovic and Zhongfa Liu for their technical support.

Keywords

  • CELLCYCLE
  • DNA
  • RNA

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