title: Sp1/NFkappaB/HDAC/miR-29b regulatory network in KIT-driven myeloid leukemia.
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.
authors.affiliation: Division of Hematology-Oncology, The Ohio State University, Columbus, OH 43210, USA. shujun.liu@osumc.edu
authors.forename: Shujun
authors.initials: S
authors.lastname: Liu
authors.forename: Lai-Chu
authors.initials: LC
authors.lastname: Wu
authors.forename: Jiuxia
authors.initials: J
authors.lastname: Pang
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Santhanam
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schwind
authors.forename: Yue-Zhong
authors.initials: YZ
authors.lastname: Wu
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hickey
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.forename: Heiko
authors.initials: H
authors.lastname: Becker
authors.forename: Kati
authors.initials: K
authors.lastname: Maharry
authors.forename: Michael D
authors.initials: MD
authors.lastname: Radmacher
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.forename: Susan P
authors.initials: SP
authors.lastname: Whitman
authors.forename: Anjali
authors.initials: A
authors.lastname: Mishra
authors.forename: Nicole
authors.initials: N
authors.lastname: Stauffer
authors.forename: Anna M
authors.initials: AM
authors.lastname: Eiring
authors.forename: Roger
authors.initials: R
authors.lastname: Briesewitz
authors.forename: Robert A
authors.initials: RA
authors.lastname: Baiocchi
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Chan
authors.forename: Peter
authors.initials: P
authors.lastname: Paschka
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
authors.forename: Ramiro
authors.initials: R
authors.lastname: Garzon
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
mesh_terms: 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
chemical_list: 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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