Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human IDH2 mutation-positive acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2 R140Q -mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with IDH2 mutation-positive advanced hematologic malignancies. SIGNIFICANCE:Mutations in IDH1/2 are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development. Cancer Discov; 7(5); 478-93.

In most mammalian species, a key process of placenta development is the fusion of trophoblast cells into a highly specialized, multinucleated syncytiotrophoblast layer, through which most of the maternofetal exchanges take place. Little is known about this process, despite the recent identification of 2 pairs of envelope genes of retroviral origin, independently acquired by the human (syncytin-1 and syncytin-2) and mouse (syncytin-A and syncytin-B) genomes, specifically expressed in the placenta, and with in vitro cell-cell fusion activity. By generating knockout mice, we show here that homozygous syncytin-A null mouse embryos die in utero between 11.5 and 13.5 days of gestation. Refined cellular and subcellular analyses of the syncytin-A-deficient placentae disclose specific disruption of the architecture of the syncytiotrophoblastcontaining labyrinth, with the trophoblast cells failing to fuse into an interhemal syncytial layer. Lack of syncytin-A-mediated trophoblast cell fusion is associated with cell overexpansion at the expense of fetal blood vessel spaces and with apoptosis, adding to the observed maternofetal interface structural defects to provoke decreased vascularization, inhibition of placental transport, and fetal growth retardation, ultimately resulting in death of the embryo. These results demonstrate that syncytin-A is essential for trophoblast cell differentiation and syncytiotrophoblast morphogenesis during placenta development, and they provide evidence that genes captured from ancestral retroviruses have been pivotal in the acquisition of new, important functions in mammalian evolution.cell-cell fusion ͉ placenta ͉ syncytiotrophoblast ͉ embryonic lethality ͉ mammalian evolution T he placenta is an autonomous and transient organ of embryonic origin (same genotype as the embryo), essentially intended for feeding and oxygenating the fetus during intrauterine life. In several mammalian species with a hemochorial placenta, including the human and mouse, the fusion of trophoblast cells into a multinucleated layer called the syncytiotrophoblast constitutes a key process of placental morphogenesis (1-4). The syncytiotrophoblast is the main fetomaternal barrier in direct contact with the maternal blood, mediating the essential trophic exchange functions between the mother and the fetus, along with hormone production and protection of the fetus against the mother's immune system. Remarkably, syncytiotrophoblasts are found in the placenta of diverse species belonging to all 4 eutherian superorders, consistent with a convergent evolution process and the presence of strong selective pressures that favor this structure (5, 6). Yet, the molecular mechanisms underlying the convergent emergence of the syncytiotrophoblast remain speculative. Vertebrate genomes harbor thousands of endogenous retrovirus (ERV) elements that display a structure close to that of the integrated proviral form of exogenous retroviruses (gag-, pol-, and env-related regions flanked by 2 LTRs) and that most probably are the remnants of p...