Background: Mutations in TDP-43 are frequently found in ALS patients. Results: A315T TDP-43 protein is elevated from this transgenic knock-in allele due to disturbed feedback regulation. Conclusion: Elevation of A315T TDP-43 was insufficient to cause ALS in this mutant. Significance: This TDP-43 allele could be valuable in determining genetic or environmental factors that cause full-blown FTLD or ALS.

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Natural killer (NK) cells are components of the innate immune system which play a pivotal role in cancer cell surveillance. Despite promising results in clinical trials, the use of NK‐based therapies is limited due to unsatisfactory efficiencies and safety issues. In recent years, exosomes have emerged as a powerful, natural therapeutic tool. Since exosomes are known to carry cargos that reflect the cellular makeup of their cell of origin, we were prompted to test whether NK‐derived exosomes (NKexo) maintain the anti‐leukemia capacity of NK‐cells. We found NK92MI‐cells to secrete large amounts of 100–200 nm cap‐shaped particles expressing exosomal and NK biomarkers (CD63, CD81, CD56). We demonstrated that NKexo exert a potent, selective, anti‐leukemia effect on all leukemia cell‐lines tested. Furthermore, NKexo eliminated leukemia cells isolated from patients with acute and chronic leukemia and inhibited hematopoietic colony growth. While leukemia cells were targeted and severely affected by NKexo, healthy B‐cells remained unaffected, indicating a selective effect. This selectivity was further confirmed by demonstrating that NKexo were specifically taken up by leukemic cells but not by healthy B‐cells. Our in vivo data support our in vitro and ex vivo findings and demonstrate improved human‐CD45+ leukemia blast counts and overall survival in NKexo treated humanized acute myeloid leukemia (HL‐60) xenograft mice thus supporting the assumption that NKexo possess an anti‐leukemia effect. Pending further analyses, our findings provide the pre‐clinical evidence needed to test the NKexo approach in future pre‐clinical and clinical studies to ultimately develop an acellular “off‐the‐shelf” product to treat leukemia.

Summary Mantle cell lymphoma (MCL) is a difficult‐to‐treat B‐cell malignancy characterized by cyclin D1 (CD1) overexpression. Targeting CD1 in MCL has been shown to be of therapeutic significance. However, treatment of MCL remains challenging since patients are still subject to early and frequent relapse of the disease. To ensure their high proliferation rate, tumour cells have increased iron needs, making them more susceptible to iron deprivation. Indeed, several iron chelators proved to be effective anti‐cancer agents. In this study, we demonstrate that the clinically approved iron chelator deferasirox (DFX) exerts an anti‐tumoural effect in MCL cell lines and patient cells. The exposure of MCL cells to clinically feasible concentrations of DFX resulted in growth inhibition, cell cycle arrest and induction of apoptosis. We show that DFX unfolds its cytotoxic effect by a rapid induction of reactive oxygen species (ROS) that leads to oxidative stress and severe DNA damage and by triggering CD1 proteolysis in a mechanism that requires its phosphorylation on T286 by glycogen synthase kinase‐3β (GSK3β). Moreover, we demonstrate that DFX mediates CD1 proteolysis by repressing the phosphatidylinositol 3‐kinase (PI3K)/AKT/GSK3β pathway via ROS generation. Our data suggest DFX as a potential therapeutic option for MCL and paves the way for more treatment options for these patients.