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Leukemia relapse is a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). We tested the potential of targeting T cell (Tc) immunoglobulin and mucin-containing molecule 3 (TIM-3) for improving graft- versus-leukemia (GVL) effects. We observed differential expression of TIM-3 ligands when hematopoietic stem cells overexpressed certain oncogenic-driver mutations. Anti-TIM-3 Ab treatment improved survival of mice bearing leukemia with oncogene- induced TIM 3 ligand expression. Conversely, leukemia cells with low ligand expression were anti-TIM-3 treatment resistant. In vitro, TIM-3 blockade or genetic deletion in [CD8.sup.+] Tc enhanced Tc activation, proliferation, and IFN-[gamma] production while enhancing GVL effects, preventing Tc exhaustion, and improving Tc cytotoxicity and glycolysis in vivo. Conversely, TIM-3 deletion in myeloid cells did not affect allogeneic Tc proliferation and activation in vitro, suggesting that anti-TIM-3 treatment-mediated GVL effects are Tc induced. In contrast to anti-programmed cell death protein 1 (anti-PD-1) and anti-cytotoxic T lymphocyte- associated protein 4 (anti-CTLA-4) treatment, anti-TIM-3-treatment did not enhance acute graft-versus-host disease (aGVHD). TIM-3 and its ligands were frequently expressed in acute myeloid leukemia (AML) cells of patients with post-allo-HCT relapse. We decipher the connections between oncogenic mutations found in AML and TIM-3 ligand expression and identify anti-TIM-3 treatment as a strategy for enhancing GVL effects via metabolic and transcriptional Tc reprogramming without exacerbation of aGVHD. Our findings support clinical testing of anti-TIM-3 Ab in patients with AML relapse after allo-HCT., Introduction Acute myeloid leukemia (AML) relapse is the main cause of death after allogeneic hematopoietic cell transplantation (allo-HCT) (1). Mechanisms promoting relapse include MHC class II downregulation (2, 3), loss [...]

Maternal-fetal calcium (Ca.sup.2+) transport in the placenta plays a critical role in maintaining fetal bone mineralization. Mutations in the gene encoding the transient receptor potential cation channel, subfamily V, member 6 (TRPV6) have been identified as causative mutations of transient neonatal hyperparathyroidism due to insufficient maternal-fetal Ca.sup.2+ transport in the placenta. In this study, we found two novel mutations in subjects that have transient neonatal hyperparathyroidism. TRPV6 carrying the mutation p.Arg390His that localizes to the outer edge of the first transmembrane domain (S1) showed impaired trafficking to the plasma membrane, whereas TRPV6 having the mutation p.Gly291Ser in the sixth ankyrin repeat (AR) domain had channel properties that were comparable those of WT channels, although the increases in steady-state intracellular Ca.sup.2+ concentration could have led to Ca.sup.2+ overload and subsequent death of cells expressing this mutant channel. These results indicate that the AR6 domain contributes to TRPV6-mediated maintenance of intracellular Ca.sup.2+ concentrations, and that this region could play a novel role in regulating the activity of TRPV6 Ca.sup.2+-selective channels. Keywords: Transient receptor potential channel (TRP channel), Maternal-fetal calcium transport, Transient neonatal hyperparathyroidism (TNHP), Patch-clamp recording, Membrane trafficking, Author(s): Yoshiro Suzuki[sup.1,2,3], Hirotake Sawada[sup.4], Tomoko Tokumasu[sup.5], Shigeru Suzuki[sup.6,7], Shinsuke Ninomiya[sup.8], Masaru Shirai[sup.6], Tokuo Mukai[sup.6,9], Claire T. Saito[sup.2], Gen Nishimura[sup.10] and Makoto Tominaga[sup.2,3] Background Calcium (Ca[sup.2+]) is essential for many [...]

Programmed cell death (PCD) is a suicide mechanism adopted by multicellular organisms that is essential for development and resistance to different forms of stress. In plants, PCD is involved from embryogenesis to death of the whole plant. PCD is genetically regulated and the molecular pathways involved in different forms of this process in animals are relatively more understood than in plants. At the morphological level, apoptosis, one of the forms of PCD in animals, and plant PCD have some similarities such as cell shrinkage, shrinkage of the nucleus, and DNA fragmentation. Because morphological characteristics are a product of the genetically encoded PCD mechanism, it is of interest to figure out how much of the apoptotic pathway is shared with plant PCD in terms of the genes involved. Evidence of some level of similarities has been gathered in the last decade, supporting conservation during signaling, regulation, and execution of apoptosis and plant PCD. A continued search into the genomes of plants has provided insights about homologues of apoptosis genes present in plants, and functional analysis provides evidence about which genes are carrying out similar roles during apoptosis and plant PCD. This review is aimed at updating on the progress of plant PCD mechanism research and highlighting some of the similarities and differences between plant and mammalian PCD mechanisms, with special focus on the commonalities. Key words: programmed cell death, apoptosis, caspase-like enzymes, regulation, signaling, execution. La mort cellulaire programmee (MCP) constitue un mecanisme de suicide adopte par les organismes multicellulaires qui est essentielle au developpement et a la resistance a differentes formes de stress. Chez les vegetaux, la MCP est impliquee de l'embryogenese a la mort complete de la plante. La MCP est regulee genetiquement et les sentiers moleculaires impliques dans les differentes formes de ce processus chez les animaux sont relativement mieux compris que chez les plantes. Sur le plan morphologique, l'apoptose, une des formes de MCP chez les animaux, et la MCP chez les vegetaux partagent certaines similarites comme la retraction cellulaire, la retraction nucleaire et la fragmentation de l'ADN. Puisque ces caracteristiques morphologiques sont issues du mecanisme de MCP code genetiquement, il est d'interet de determiner la proportion du sentier d'apoptose qui est partagee avec la MCP des vegetaux en termes de genes impliques. Des preuves d'un certain niveau de similarite ont ete recoltees au cours de la derniere decennie, ce qui appuie la conservation des processus durant la signalisation, la regulation et l'execution de l'apoptose et de la MCP des vegetaux. Une recherche en continu dans les genomes des plantes a donne un apercu des homologues des genes de l'apoptose presents chez les plantes, et l'analyse fonctionnelle permet de determiner quels genes jouent des roles similaires durant l'apoptose et la MCP chez les vegetaux. Cet article de synthese vise a mettre a jour l'information relative a la recherche portant sur la MCP chez les vegetaux, et souligne certaines similarites et differences entre les mecanismes de MCP chez les vegetaux et les mammiferes, et plus particulierement sur les points communs. [Traduit par la Redaction] Mots-cles: mort cellulaire programmee, apoptose, enzymes de type caspase, regulation, signalisation, execution., Introduction Programmed cell death (PCD) is a genetically regulated process responsible for the elimination of undesirable cells in eukaryotes; it is necessary for development and survival. It is also essential [...]