Dataset Information

Stabilization of NF-?B-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia.

ABSTRACT: Canonical NF-?B signaling is constitutively activated in acute myeloid leukemia (AML) stem cells and is required for maintenance of the self-renewal of leukemia stem cells (LSCs). However, any potential role for NF-?B non-canonical signaling in AML has been largely overlooked. Here, we report that stabilization of NF-?B-inducing kinase (NIK) suppresses AML. Mechanistically, stabilization of NIK activates NF-?B non-canonical signaling and represses NF-?B canonical signaling. In addition, stabilization of NIK-induced activation of NF-?B non-canonical signaling upregulates Dnmt3a and downregulates Mef2c, which suppresses and promotes AML development, respectively. Importantly, by querying the connectivity MAP using up- and downregulated genes that are present exclusively in NIK-stabilized LSCs, we discovered that verteporfin has anti-AML effects, suggesting that repurposing verteporfin to target myeloid leukemia is worth testing clinically. Our data provide a scientific rationale for developing small molecules to stabilize NIK specifically in myeloid leukemias as an attractive therapeutic option.

SUBMITTER: Xiu Y

PROVIDER: S-EPMC5810947 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Publications

Stabilization of NF-κB-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia.

Xiu Yan Y Dong Qianze Q Li Qingchang Q Li Fengyin F Borcherding Nick N Zhang Weizhou W Boyce Brendan B Xue Hai-Hui HH Zhao Chen C

Cell reports 20180101 2

Canonical NF-κB signaling is constitutively activated in acute myeloid leukemia (AML) stem cells and is required for maintenance of the self-renewal of leukemia stem cells (LSCs). However, any potential role for NF-κB non-canonical signaling in AML has been largely overlooked. Here, we report that stabilization of NF-κB-inducing kinase (NIK) suppresses AML. Mechanistically, stabilization of NIK activates NF-κB non-canonical signaling and represses NF-κB canonical signaling. In addition, stabiliz ...[more]

PMID: 29320732

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Project description:Rearrangement of the mixed lineage leukemia (MLL; also known as lysine methyltransferase 2A) gene is a recurrent genomic aberration in acute myeloid leukemia (AML). MLLT3, super elongation complex subunit (AF9) is one of the most common MLL fusion partners in AML. The present study aimed to explore the aberrant expression of genes associated with the MLL‑AF9 translocation and identified potential new targets for the therapy of AML with MLL‑AF9 translocation. The transcriptomic and epigenetic datasets were downloaded from National Center of Biotechnology Information Gene Expression Omnibus (GEO) database. Differentially expressed genes were obtained from two independent datasets (GSE68643 and GSE73457). Gene Ontology biological process and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed using the Database for Annotation, Visualization and Integrated Discovery. MLL‑AF9‑associated chromatin immunoprecipitation sequencing (ChIP‑Seq) data was analyzed and identified binding sites for MLL‑AF9 and wild type MLL (MLL WT). The ChIP‑Seq of histone modification data was downloaded from the GEO database, including histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 79 dimethylation (H3K79me2) and histone 3 lysine 27 acetylation (H3K27ac), was used for comparing histone modification marks between the MLL‑AF9 leukemia cells and normal hematopoietic cells at MLL‑AF9 and MLL WT binding sites. The differentially expressed genes with the same trend in H3K79me2, H3K27ac and H3K4me3 alteration were identified as potential MLL‑AF9 direct target genes. Upon validation using RNA‑Seq data from the Therapeutically Applicable Research to Generate Effective Treatments AML project, eight potential direct target genes of MLL‑AF9 were identified and further confirmed in MLL‑AF9 mouse model using reverse transcription‑quantitative polymerase chain reaction. These genes may have a critical role in AML with MLL‑AF9 translocation.

Dataset Information

Stabilization of NF-?B-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia.

Publications

Stabilization of NF-κB-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia.

Similar Datasets

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