A cooperative microRNA-tumor suppressor gene network in acute T-cell lymphoblastic leukemia (T-ALL)

Abstract

The importance of individual microRNAs (miRNAs) has been established in specific cancers. However, a comprehensive analysis of the contribution of miRNAs to the pathogenesis of any specific cancer is lacking. Here we show that in T-cell acute lymphoblastic leukemia (T-ALL), a small set of miRNAs is responsible for the cooperative suppression of several tumor suppressor genes. Cross-comparison of miRNA expression profiles in human T-ALL with the results of an unbiased miRNA library screen allowed us to identify five miRNAs (miR-19b, miR-20a, miR-26a, miR-92 and miR-223) that are capable of promoting T-ALL development in a mouse model and which account for the majority of miRNA expression in human T-ALL. Moreover, these miRNAs produce overlapping and cooperative effects on tumor suppressor genes implicated in the pathogenesis of T-ALL, including IKAROS (also known as IKZF1), PTEN, BIM, PHF6, NF1 and FBXW7. Thus, a comprehensive and unbiased analysis of miRNA action in T-ALL reveals a striking pattern of miRNA-tumor suppressor gene interactions in this cancer.

Serum Levels of miR-19b and miR-146a as Prognostic Biomarkers for Non-Small Cell Lung Cancer

“…lymphoma (Mavrakis et al 2011) and is involved in invasion and metastasis of cervical cancer . As a tumor suppressor gene, the miR-146a is downregulated in various types of cancer cells (Chen et al 2013a;Zhou et al 2013).…”

MicroRNA-128-3p is a novel oncomiR targeting PHF6 in T-cell acute lymphoblastic leukemia

“…Interaction score cutoff values were determined as such to minimize false positive hits at the expense of missing a few true interactions (false negative results). This probably explains why miR-20a and miR-26a, the only reported PHF6-targeting miRNAs, 12 were not retained as positive hits in our screen. However, our results underscore the value of an unbiased screening method to detect novel, predicted as well as non-predicted, miRNA-target gene interactions.…”

“…We, therefore, evaluated miRNA expression levels in a genetically well-characterized cohort of patients (n=50) with T-ALL as well as in subsets of normal, flow sorted thymocytes (data previously reported data by Mavrakis et al 12 and see Methods). Following the assumption that miRNAs with a potential oncogenic effect should show significant expression in primary T-ALL samples, we identified seven of the 23 miRNAs selected from the miRNA library screen which were among the top 50% expressed miRNAs in the T-ALL patients' samples (Online Supplementary Table S2).…”

Endothelial miR-17∼92 cluster negatively regulates arteriogenesis via miRNA-19 repression of WNT signaling

“…The region encoding for this cluster, C13orf25, is amplified in multiple types of lymphomas, including diffuse large B-cell lymphoma, follicular lymphoma, and some solid tumors (6). Its wide spectrum of validated targets implies effects on multiple signaling pathways, such as BMP, TGF, and PI3K signaling involved in development and disease (7)(8)(9)(10)(11)(12). It is well known that individual miRNAs of this cluster can cooperate or work independently to efficiently modulate multiple signaling pathways, as has been demonstrated for miR-19, which drives the oncogenic ability of this cluster in the context of a MYC-driven B-cell lymphoma (9).…”