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~363 Xpcl1 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~363 Xpcl1 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 p27 Kip1 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.