MicroRNA and transcription factor co-regulatory network analysis reveals miR-19 inhibits CYLD in T-cell acute lymphoblastic leukemia.

Nucleic acids research

PubMedID: 22362744

Ye H, Liu X, Lv M, Wu Y, Kuang S, Gong J, Yuan P, Zhong Z, Li Q, Jia H, Sun J, Chen Z, Guo AY. MicroRNA and transcription factor co-regulatory network analysis reveals miR-19 inhibits CYLD in T-cell acute lymphoblastic leukemia. Nucleic Acids Res. 2012;40(12):5201-14.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. The understanding of its gene expression regulation and molecular mechanisms still remains elusive. Started from experimentally verified T-ALL-related miRNAs and genes, we obtained 120 feed-forward loops (FFLs) among T-ALL-related genes, miRNAs and TFs through combining target prediction. Afterwards, a T-ALL miRNA and TF co-regulatory network was constructed, and its significance was tested by statistical methods. Four miRNAs in the miR-17-92 cluster and four important genes (CYLD, HOXA9, BCL2L11 and RUNX1) were found as hubs in the network. Particularly, we found that miR-19 was highly expressed in T-ALL patients and cell lines. Ectopic expression of miR-19 represses CYLD expression, while miR-19 inhibitor treatment induces CYLD protein expression and decreases NF-?B expression in the downstream signaling pathway. Thus, miR-19, CYLD and NF-?B form a regulatory FFL, which provides new clues for sustained activation of NF-?B in T-ALL. Taken together, we provided the first miRNA-TF co-regulatory network in T-ALL and proposed a model to demonstrate the roles of miR-19 and CYLD in the T-cell leukemogenesis. This study may provide potential therapeutic targets for T-ALL and shed light on combining bioinformatics with experiments in the research of complex diseases.