The miR-106a~363 miRNA cluster induces murine T cell lymphoma despite transcriptional activation of the p27 cell cycle inhibitor.

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 that are predicted to be both oncogenic and tumor suppressive, yet little is known about their physiological functions . Mature miR-106a~363 () miRNAs are processed from an intragenic, non-protein encoding gene referred to as Xpcl1 (or ), situated at an X-chromosomal locus frequently targeted by retroviruses in murine lymphomas. The oncogenic potential of miR-106a~363 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 at this stage impairs thymocyte maturation and induces T-cell lymphomas. Surprisingly, miR-106a~363 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 deletion dramatically accelerated lymphomagenesis, indicating that p27 is rate limiting for tumor development by . Whereas down-regulation of miR-106a~363 is important for normal T cell differentiation and for the prevention of lymphomas, eliminating p27 reveals 's full oncogenic potential.