The miR-106a~363Xpcl1 miRNA cluster induces murine T cell lymphoma despite transcriptional activation of the p27Kip1 cell cycle inhibitor
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Daniel A. Kuppers1, Thomas M. Schmitt1, Harry C. Hwang2, Lavanya Samraj3, Bruce E. Clurman1 and Matthew L. Fero4
1Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
2Phenopath Laboratories, Seattle, Washington, USA
3University of Washington, Seattle, Washington, USA
4University of New Mexico, Albuquerque, New Mexico, USA
Matthew L. Fero, email: firstname.lastname@example.org
Keywords: cell cycle, mouse model, T cell development, oncogene, non-coding RNA
Received: November 15, 2016 Accepted: March 22, 2017 Published: April 07, 2017
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.
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