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Sp1/NFkappaB/HDAC/miR-29b regulatory network in KIT-driven myeloid leukemia.

Authors :
Liu S
Wu LC
Pang J
Santhanam R
Schwind S
Wu YZ
Hickey CJ
Yu J
Becker H
Maharry K
Radmacher MD
Li C
Whitman SP
Mishra A
Stauffer N
Eiring AM
Briesewitz R
Baiocchi RA
Chan KK
Paschka P
Caligiuri MA
Byrd JC
Croce CM
Bloomfield CD
Perrotti D
Garzon R
Marcucci G
Source :
Cancer cell [Cancer Cell] 2010 Apr 13; Vol. 17 (4), pp. 333-47.
Publication Year :
2010

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.<br /> (Copyright 2010 Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1878-3686
Volume :
17
Issue :
4
Database :
MEDLINE
Journal :
Cancer cell
Publication Type :
Academic Journal
Accession number :
20385359
Full Text :
https://doi.org/10.1016/j.ccr.2010.03.008