Dataset Information

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.

SUBMITTER: Liu S

PROVIDER: S-EPMC2917066 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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

Liu Shujun S 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

Cancer cell 20100401 4

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 bi ...[more]

PMID: 20385359

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Project description:BackgroundAcute myeloid leukemia (AML) is initiated and maintained by a unique, small subset of leukemia stem cells (LSCs). LSCs are characterized by unrestricted self-renewal and contribute to the malignancy of leukemia. Aberrant protein fucosylation is associated with AML progression. However, it is still less understood that the miR-29b/Sp1/FUT4 crosstalk involved in the fucosylation-mediated LSCs malignancy in AML.MethodsAML cell lines were sorted by magnetic microbeads to obtain the CD34?+?CD38- sub-population. The key biomarkers for LSCs were identified by flow cytometry. Fucosyltransferase genes were screened by qRT-PCR, and FUT4 was focused. Effect of FUT4 on LSCs malignancy was determined by CCK8 assay, sphere formation assay, immunofluorescence staining, apoptosis and in vivo xenografts experiments. The linkage of FUT4 promoter and Sp1 was confirmed by dual-luciferase reporter gene assay. ChIP-PCR assay was used to show the directly binding of Sp1 and FUT4 promoter. Activity of Wnt//?-catenin pathway was determined by western blot. Overall survival curves were diagrammed by Kaplan-Meier analysis.ResultsHere, the expressional profiles of 11 fucosyltransferase genes were different comparing LSCs and non-LSCs of KG-1a and MOLM13 cells, whereas CD34?+?CD38- cells exhibited higher expression of FUT4. Functionally, alteration of FUT4 in CD34?+?CD38- cells modulated LSCs malignant behaviors both in vitro and in vivo. Transcriptional inhibitor actinomycin D (Act D) or translational inhibitor cycloheximide (CHX) prevented LSCs progression, and Sp1 was identified as the efficient regulator of FUT4 transcription. Moreover, miR-29b directly affected the binding of Sp1 and FUT4 promoter region, which further mediated LSCs proliferation, apoptosis and drug-resistance through fucosylated-CD44 via activation of Wnt/?-catenin pathway. Clinically, Sp1 and FUT4 were up-regulated and positively correlated with poor overall survival of AML patients.ConclusionThese data indicated that miR-29b/Sp1/FUT4 axis promoted the malignant behaviors of LSCs by regulating fucosylated CD44 via Wnt/?-catenin pathway. Identifying LSCs surface markers and targeting LSCs were important for the development of potential therapies in AML.

Dataset Information

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

Publications

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

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