Myc depletion induces a pluripotent dormant state mimicking diapause

Mouse embryonic stem cells (ESCs) are maintained in a naive ground state of pluripotency in the presence of MEK and GSK3 inhibitors. Here, we show that ground-state ESCs express low Myc levels. Deletion of both c-myc and N-myc (dKO) or pharmacological inhibition of Myc activity strongly decreases transcription, splicing, and protein synthesis, leading to proliferation arrest. This process is reversible and occurs without affecting pluripotency, suggesting that Myc-depleted stem cells enter a state of dormancy similar to embryonic diapause. Indeed, c-Myc is depleted in diapaused blastocysts, and the differential expression signatures of dKO ESCs and diapaused epiblasts are remarkably similar. Following Myc inhibition, pre-implantation blastocysts enter biosynthetic dormancy but can progress through their normal developmental program after transfer into pseudo-pregnant recipients. Our study shows that Myc controls the biosynthetic machinery of stem cells without affecting their potency, thus regulating their entry and exit from the dormant state.This work was supported by the FOR2033 and SFB873 funded by the Deutsche Forschungsgemeinschaft (DFG), the Dietmar Hopp Foundation (all to A.T.), and the Wellcome Trust (to A.S.)

Short-term assays for detection of conditional cancerogens. I. Construction of DR-CAT Raji cells and some of their characteristics as tester cells.

A number of agents including the tumor promoter 12-0-tetradecanoyl-phorbol-13-acetate (TPA) can induce an abortive virus cycle in the EBV-non-producer Burkitt's-lymphoma line Raji. Two distant regions, DL and DR, of the EBV genome with almost complete homology carry strong promoters which are induced in an abortive or lytic cycle and additionally function as lytic origins of viral DNA replication. To set up a system in which the activity of EBV-inducing agents can be measured in a quantitative and reproducible fashion, we generated a cell line which carries multiple copies of a DR-promoter chloramphenicol-acetyltransferase (CAT) construct on an episomal vector. CAT activity is low in untreated cells, but high upon treatment of the cells with various EBV-inducing agents. Combinations of different agents can produce an over-additive effect. The Raji-DR-CAT cell line may provide a simple quantitative and reproducible test system for EBV-inducing agents, especially for tumor promoters which activate protein kinases C

Correction: CRISPR/Cas9-edited NSG mice as PDX models of human leukemia to address the role of niche-derived SPARC (Leukemia, (2018), 32, 4, (1048-1051), 10.1038/leu.2017.346).

This article was originally published under NPG’s License to Publish, but has now been made available under a CCBY license. The PDF and HTML versions of the paper have been modified accordingly