The ERG (ETS-related gene) transcription factor is linked to various types of cancer, including leukemia. However, the specific ERG domains and co-factors contributing to leukemogenesis are poorly understood. Drug targeting a transcription factor such as ERG is challenging. Our study reveals the critical role of a conserved amino acid, proline, at position 199, located at the 3' end of the PNT (pointed) domain, in ERG's ability to induce leukemia. P199 is necessary for ERG to promote self-renewal, prevent myeloid differentiation in hematopoietic progenitor cells, and initiate leukemia in mouse models. Here we show that P199 facilitates ERG's interaction with the NCoR-HDAC3 co-repressor complex. Inhibiting HDAC3 reduces the growth of ERG-dependent leukemic and prostate cancer cells, indicating that the interaction between ERG and the NCoR-HDAC3 co-repressor complex is crucial for its oncogenic activity. Thus, targeting this interaction may offer a potential therapeutic intervention.
© 2023. Springer Nature Limited.

Human germline-soma segregation occurs during weeks 2-3 in gastrulating embryos. Although direct studies are hindered, here, we investigate the dynamics of human primordial germ cell (PGCs) specification using in vitro models with temporally resolved single-cell transcriptomics and in-depth characterisation using in vivo datasets from human and nonhuman primates, including a 3D marmoset reference atlas. We elucidate the molecular signature for the transient gain of competence for germ cell fate during peri-implantation epiblast development. Furthermore, we show that both the PGCs and amnion arise from transcriptionally similar TFAP2A-positive progenitors at the posterior end of the embryo. Notably, genetic loss of function experiments shows that TFAP2A is crucial for initiating the PGC fate without detectably affecting the amnion and is subsequently replaced by TFAP2C as an essential component of the genetic network for PGC fate. Accordingly, amniotic cells continue to emerge from the progenitors in the posterior epiblast, but importantly, this is also a source of nascent PGCs.
© 2023 Castillo-Venzor et al.

Human germline-soma segregation occurs during weeks 2-3 in gastrulating embryos. While direct studies are hindered, here we investigate the dynamics of human primordial germ cell (PGCs) specification using in vitro models with temporally resolved single-cell transcriptomics and in-depth characterisation to in vivo datasets from human and non-human primates, including a 3D marmoset reference atlas. We elucidate the molecular signature for the transient gain of competence for germ cell fate during peri-implantation epiblast development. Further, we show that both the PGCs and amnion arise from transcriptionally similar TFAP2A positive progenitors at the posterior end of the embryo. Notably, genetic loss of function experiments show that TFAP2A is crucial for initiating the PGC fate without detectably affecting the amnion, and its subsequently replaced by TFAP2C as an essential component of the genetic network for PGC fate. Accordingly, amniotic cells continue to emerge from the progenitors in the posterior epiblast, but importantly, this is also a source of nascent PGCs.

Investigations of the human germline and programming are challenging because of limited access to embryonic material. However, the pig as a model may provide insights into transcriptional network and epigenetic reprogramming applicable to both species. Here we show that, during the pre- and early migratory stages, pig primordial germ cells (PGCs) initiate large-scale epigenomic reprogramming, including DNA demethylation involving TET-mediated hydroxylation and, potentially, base excision repair (BER). There is also macroH2A1 depletion and increased H3K27me3 as well as X chromosome reactivation (XCR) in females. Concomitantly, there is dampening of glycolytic metabolism genes and re-expression of some pluripotency genes like those in preimplantation embryos. We identified evolutionarily young transposable elements and gene coding regions resistant to DNA demethylation in acutely hypomethylated gonadal PGCs, with potential for transgenerational epigenetic inheritance. Detailed insights into the pig germline will likely contribute significantly to advances in human germline biology, including in vitro gametogenesis.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Although the available treatment options have expanded, the survival of patients with metastatic renal cell carcinoma (RCC) remains poor. As patients with RCC lack responsiveness to chemotherapy or radiation, therapeutic options predominantly include surgical interventions and immunomodulatory approaches, including the administration of tyrosine kinase inhibitors (TKIs) such as sunitinib. Natural killer (NK) cells have been reported to be key players in TKI-mediated off-target effects on the immune system. However, only limited information is available regarding the possible impact of sunitinib on the function of NK cells of individual patients. The present study reports on the immunomonitoring results of three patients with metastatic RCC who underwent sunitinib treatment. These results were compared with age-matched, healthy controls in terms of the immune status of T, B and NK cells, focusing on functional in vitro analyses of NK cells. In all three patients, NK cell number, subset distribution and function, as measured by cluster of differentiation 107a degranulation, did not exhibit any significant alterations as a result of sunitinib treatment. These results indicate that sunitinib does not negatively affect NK cell function, which supports the pursuit of therapeutic modalities that combine immunomodulation and NK cell-stimulating approaches.