Abstract A24: Interaction of Mir-106A~363xpcl1 and P27kip1 in Thymopoiesis and Lymphomagenesis

Abstract The Xpcl1 (Kis2) gene encodes the miR-106a~363 miRNA cluster in mice. Although it was first identified as common integration site of the M-MuLV retrovirus in tumors from p27Kip1 (Cdkn1b) knockout mice, the nature of its interaction with cell cycle genes is uncertain. The miR-106a~363 miRNAs are highly conserved across species, implying an important role in normal biological processes. However, in the absence of a reported phenotype in knockout mice, its normal function is unclear. We examined miR-106a~363 expression in developing T lymphocytes and found that it is highly expressed in immature T-cells but is repressed at the CD4+/CD8+ double positive (DP) stage of thymopoiesis. Using a T cell specific Xpcl1 transgene, we found that forced expression of miR-106a~363 altered the distribution of T cell subsets. Xpcl1 repressed T-cell receptor expression and directly targeted the CD69 cell surface protein. This causes accumulation of DP thymocytes through complementary mechanisms. We show that, in developing T-cells, p27Kip1 is differentially regulated due to variation in expression of FoxO family transcription factors. Likewise, p27 is upregulated at the transcriptional level by Xpcl1, which is surprising since this should have a tumor suppressor effect. Nonetheless, miR-106a~363 transgenic (Lx) mice developed spontaneous high grade T cell lymphomas. The combination of p27Kip1 deletion with miR-106a~363 overexpression, markedly accelerated lymphoma development, confirming cooperation of these two mutations. We conclude that deletion of p27Kip1 directly overcomes a tumor-suppressor activity of miR-106a~363, whereas the principal oncogenic function of the miRNA cluster remains unknown. Citation Format: Daniel Kuppers, Thomas Schmitt, Bruce Clurman, Harry Hwang, Matthew L. Fero. Interaction of miR-106a~363Xpcl1 and p27Kip1 in thymopoiesis and lymphomagenesis [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr A24.