The miR-106a~363Xpcl1 miRNA cluster induces murine T cell lymphoma despite transcriptional activation of the p27Kip1 cell cycle inhibitor.

Daniel A Kuppers,Matthew L Fero,Bruce E Clurman,Lavanya Samraj,Harry C Hwang,Thomas M Schmitt

doi:10.18632/oncotarget.16932

Daniel A Kuppers, Matthew L Fero + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.16932

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Abstract

The miR-106a~363 cluster encodes 6 miRNAs on the X-chromosome which are abundant in blood cells and overexpressed in a variety of malignancies. The constituent miRNA of miR-106a~363 have functional activities in vitro that are predicted to be both oncogenic and tumor suppressive, yet little is known about their physiological functions in vivo. Mature miR-106a~363 (Mirc2) miRNAs are processed from an intragenic, non-protein encoding gene referred to as Xpcl1 (or Kis2), situated at an X-chromosomal locus frequently targeted by retroviruses in murine lymphomas. The oncogenic potential of miR-106a~363Xpcl1 has not been proven, nor its potential role in T cell development. We show that miR106a~363 levels normally drop at the CD4+/CD8+ double positive (DP) stage of thymocyte development. Forced expression of Xpcl1 at this stage impairs thymocyte maturation and induces T-cell lymphomas. Surprisingly, miR-106a~363Xpcl1 also induces p27 transcription via Foxo3/4 transcription factors. As a haploinsufficient tumor suppressor, elevated p27 is expected to inhibit lymphomagenesis. Consistent with this, concurrent p27Kip1 deletion dramatically accelerated lymphomagenesis, indicating that p27 is rate limiting for tumor development by Xpcl1. Whereas down-regulation of miR-106a~363 is important for normal T cell differentiation and for the prevention of lymphomas, eliminating p27 reveals Xpcl1's full oncogenic potential.

Highlights

The X-chromosomal miR-106a~363 miRNA cluster is comprised of 6 mature miRNAs which are highly conserved from mice to humans
In this study we show that miR106a~363 is down regulated during thymocyte differentiation and that this impacts normal T cell development and prevents the development of lymphomas
Other than retroviral mutagenesis studies, which typically induce dozens of mutations, the Lx transgenic mouse is the first example of T cell lymphomas induced by aberrant expression of noncoding RNA

Summary

Introduction

The X-chromosomal miR-106a~363 miRNA cluster is comprised of 6 mature miRNAs which are highly conserved from mice to humans. Constituents of the miR-106a~363 cluster, and its autosomal paralogs (miR-106b~25 and miR-17~92), include some of the most highly expressed miRNAs in blood cells [1]. High levels of miR-106a~363 miRNA have been observed in a variety of human malignancies. In anaplastic large cell lymphoma (ALCL), an aggressive human T cell lymphoma, miR-106a~363 is highly expressed (especially miR-106a and miR-20b), whereas the same tumor type typically exhibits a PI3K-dependent loss of the Cdk inhibitor protein p27Kip (Cdkn1b) [5,6,7]. B cell lymphomas may express varying levels of miR-106a~363 or its paralogs. While genetic evidence of the oncogenicity of miR-106a~363 in human malignancies is lacking, amplifications of the miR-17~92 paralog has been documented in diffuse large B cell lymphomas [9]

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