TERT, the protein component of telomerase 1,2 , serves to maintain telomere function through the de novo addition of telomere repeats to chromosome ends and is reactivated in 90% of human cancers. In normal tissues, TERT is expressed in stem cells and in progenitor cells 3 , but its role in these compartments is not fully understood. Here, we show that conditional transgenic induction of TERT in mouse skin epithelium causes a rapid transition from telogen, the resting phase of the hair follicle cycle, to anagen, the active phase, thereby facilitating robust hair growth. TERT overexpression promotes this developmental transition by causing proliferation of quiescent, multipotent stem cells in the hair follicle bulge region. This new function for TERT does not require the telomerase RNA component (TERC), which encodes the template for telomere addition, and therefore operates through a novel mechanism independent of its activity in synthesizing telomere repeats. These data indicate that, in addition to its established role in extending telomeres, TERT can promote proliferation of resting stem cells through a non-canonical pathway. Keywords telomerase; telomere; stem cell; hair follicle; epidermis In stem cell and progenitor cell compartments 3-5 , TERT serves an important role in keeping telomeres sufficiently long and stable to prevent the adverse consequences of dysfunctional telomeres on cell viability and chromosomal stability 6-8 . However, the need for expression of TERT in tissue stem cells and progenitor cells with long telomeres is less clear, especially in laboratory mice, whose telomeres are significantly longer than those of humans (40-60kb vs. 5-15kb). Moreover, recent findings indicate that TERT promotes tumor development even in settings of ample telomere reserve, although the mechanisms underlying these telomere length-independent activities of TERT remain unclear 9-13 . We therefore hypothesized that TERT may exert effects in stem cell and progenitor cell compartments that could explain both its regulation during lineage development and its poorly understood telomere lengthindependent activities.To test this hypothesis, we turned to the mammalian hair follicle, an organ that harbors tightly regulated multipotent stem cells and that cycles between telogen and anagen 14 . Initiation of a new anagen cycle depends upon activation of a small number of quiescent stem cells that reside

Telomeres are comprised of TTAGGG nucleotide repeats and a large protein complex that together protect chromosomal ends. Telomeres shorten progressively with cell division in the absence of telomerase, a reverse transcriptase that synthesizes telomere repeats. Critical telomere shortening has potent effects on cancer development, either blocking cancer progression by impairing proliferation and survival or promoting cancer by enhancing chromosomal instability. Although telomerase is upregulated in the vast majority of human cancers, where it is thought to endow cancer cells with unlimited proliferative capacity, the regulation of telomerase during the course of normal lineage development or during leukemogenesis remains unclear. Here, we show that expression of TERT, the protein catalytic subunit of telomerase, is tightly regulated during myeloid development in both human and mouse. Real time PCR analysis of RNA from purified human stem cell and progenitor cell populations showed that TERT mRNA was highest in human HSCs (100%, values normalized to HSC). TERT mRNA remained high in common myeloid progenitors (CMP, 47%), but was dramatically decreased with differentiation to granulocyte-monocyte progenitors (GMP, 3%) or megakaryocyte-erythroid progenitors (MEP, 0.2%). TERT was similarly down regulated during normal myeloid development in mouse bone marrow. In marked contrast, TERT was reactivated in leukemic GMP in a transgenic Faslpr/lprhMRP8BCL2 mouse model of acute myelogenous leukemia. Notably, transplantation experiments demonstrated that leukemic GMP provided the most robust leukemic transplantation potential compared with HSC or blasts suggesting that TERT reactivation may provide an important final step in leukemic pathogenesis by enhancing the replicative life-span of leukemic progenitors. Currently, we are in the process of assessing TERT regulation in human leukemic progenitors isolated from patients with CML in chronic, accelerated and blast phases. Together, these data indicate that TERT is most highly expressed in stem cells and multipotent progenitors. This pattern of TERT expression may reflect a need for efficient telomere maintenance in these stem/progenitor compartments. Furthermore, these data are consistent with our recent data showing novel, telomere length-independent functions for TERT in stem/progenitor cell compartments.