Sp1/NFkappaB/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 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.
Liu
Shujun
S
Division of Hematology-Oncology, The Ohio State University, Columbus, OH 43210, USA. shujun.liu@osumc.edu
Wu
Lai-Chu
LC
Pang
Jiuxia
J
Santhanam
Ramasamy
R
Schwind
Sebastian
S
Wu
Yue-Zhong
YZ
Hickey
Christopher J
CJ
Yu
Jianhua
J
Becker
Heiko
H
Maharry
Kati
K
Radmacher
Michael D
MD
Li
Chenglong
C
Whitman
Susan P
SP
Mishra
Anjali
A
Stauffer
Nicole
N
Eiring
Anna M
AM
Briesewitz
Roger
R
Baiocchi
Robert A
RA
Chan
Kenneth K
KK
Paschka
Peter
P
Caligiuri
Michael A
MA
Byrd
John C
JC
Croce
Carlo M
CM
Bloomfield
Clara D
CD
Perrotti
Danilo
D
Garzon
Ramiro
R
Marcucci
Guido
G
D045744:Cell Line, Tumor; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D006655:Histone Deacetylases / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D007136:Immunoglobulins / Q000502:physiology*; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000503:physiopathology; D035683:MicroRNAs / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D014158:Transcription, Genetic
D007136:Immunoglobulins; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; C090698:SP1 antigen; D019009:Proto-Oncogene Proteins c-kit; D006655:Histone Deacetylases
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