G0/G1 Switch Gene 2 (G0S2) Is a Positive Regulator of Quiescence in Hematopoietic Stem Cells and Naïve T Cells.

Abstract 2538

Poster Board II-515

The G0/G1 switch gene 2 (G0S2) was identified in blood mononuclear cells activated with mitogens. G0S2 is a small basic protein located in ER/Golgi in mouse fibroblast. Even though G0S2 is upregulated in inflammatory processes (i.e. rheumatoid arthritis, psoriasis, endometriosis) and by all-trans-retinoic acid treatment in acute promyelocytic leukemia cells, its role in the proliferation of hematopoietic stem cells (HSC) and T lymphocytes is largely unknown. Similarly to HSC, a delicate balance between quiescence and homeostatic proliferation maintains the T cell pool over time. An emerging paradigm suggests that cellular quiescence is an actively regulated state. G0S2 expression in bone marrow (BM) cells is downregulated following cytoablation, suggesting a role in the maintenance of stem cell quiescence. Gain-of function experiments, using retroviral gene transfer and BM transplantation, showed that G0S2 increased number of Lin- Sca-1+ c-kit+ cells in BM by inhibiting their proliferation at steady state. In addition, ectopic G0s2 expression inhibits homeostatic expansion of CD11b+ Gr-1+ and CD3+ cells. Competitive BM transplantation showed that cells overexpressing G0S2 are outcompeted by wild type BM cells due to lower proliferative potential, based on in vivo BrdU incorporation experiments. Inhibition of T cell proliferation by ectopic G0S2 expansion is consistent with suppression of G0S2 transcription in naïve CD8+ T cells upon T-cell receptor activation via MAPK and calcium-calmodulin pathways, suggesting that G0S2 also maintains quiescence of naïve T cells. G0S2 expression is silenced in myeloid and lymphoid leukemic cell lines by gene methylation, supporting a leukemogenic role. Collectively, our study uncovered an important role of G0S2 in normal and malignant proliferation of HSC and T cells.