Nanog is a key molecule involved in the maintenance of the self-renewal of undifferentiated embryonic stem (ES) cells. In this work we investigate whether Nanog can enhance self-renewal in hematopoietic stem cells. Contrary to our expectation, no positive effect of Nanog transduction was detected in bone marrow reconstitution assays. However, recipients of Nanog-transduced (Nanog) hematopoietic stem cells (HSCs) invariantly develop a unique disorder typified by an atrophic thymus occupied by Nanog-expressing gammadeltaT-cell receptor-positive (TCR(+)) cells (Nanog T cells). All thymi are eventually occupied by Nanog T cells with CD25(+)CD44(+) surface phenotype that home selectively to the thymus on transfer and suppress normal thymocyte development, which is partly ascribed to destruction of the microenvironment in the thymus cortex. Moreover, this initial disorder invariantly develops to a lymphoproliferative disorder, in which Nanog T cells undergo unlimited proliferation in the peripheral lymphoid tissues and eventually kill the host. This invariable end result suggests that Nanog is a candidate oncogene for gammadeltaT-cell malignancy.