NPM1-mutated acute myeloid leukemia (AML) represents one of the most frequent and biologically distinct AML entities, characterized by the aberrant cytoplasmic localization of the NPM1 mutant protein. The recent advances in molecular biology and translational research have progressively redefined the clinical management of this disease. This narrative review summarizes the evolution of NPM1-mutated AML over the last two decades, focusing on the transition from immunohistochemical observations to modern genetics-based and measurable residual disease (MRD)-driven approaches. We discuss the biological role of mutant NPM1, the prognostic impact of co-occurring genetic alterations, and the integration of molecular monitoring into routine clinical practice. Particular attention is given to the prognostic and therapeutic implications of the co-mutational landscape. We also discuss emerging targeted therapies directed against key pathogenic pathways, including the menin–KMT2A axis and nuclear export machinery. Despite significant advances in risk stratification and treatment, considerable heterogeneity in clinical outcomes persists among patients with NPM1-mutated AML, indicating that genomic information obtained at diagnosis alone is insufficient to fully capture prognostic differences. Future advances will likely depend on the integration of genetic, transcriptional, and broader cellular-state information to better define biologically relevant disease states and guide more personalized therapeutic strategies.

Background: Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. Changes in the ubiquitination system in GBM cells can promote uncontrolled tumor growth and reduce the effectiveness of treatments. However, the exact targets and regulatory elements of the ubiquitin–proteasome system involved in GBM are still not well understood. Methods: All data were obtained by using in silico analysis, immunohistochemistry, Western blot, RT-qPCR, gene silencing and proliferation assay. Results: Computational and protein analyses show that aggressive gliomas have higher expression of the RING ligase RNF182, with significantly greater levels in glioblastoma (GBM) than in low-grade gliomas. Elevated RNF182 is strongly associated with GBM growth. Experiments using siRNA to inhibit RNF182 in the human glioblastoma cell line U87MG significantly reduced cell proliferation, suggesting that RNF182 promotes tumor growth and may be a potential therapeutic target. Conclusions: These findings create a connection between the ubiquitin–proteasome system and the unchecked growth observed in GBM, identifying RNF182 as a new marker associated with GBM proliferation and an additional target for GBM treatment.

Background: Recent evidence suggests that the antidepressant vortioxetine (Vx) inhibits the growth of glioblastoma (GBM), the most aggressive primary malignant tumor of the CNS. We used five patient-derived GBM cell lines to confirm the anti-GBM effect of Vx and explore its mechanism(s) of action. Methods: We performed in silico analysis, PCR, TUNEL assay, colony assay, and proliferation assay. Results: Vx potently inhibited GBM cell growth, and showed efficacy at concentrations of 0.1 μM that roughly correspond to therapeutic concentrations of Vx in major depression. Other antidepressants, i.e., fluoxetine and duloxetine, inhibited GBM cell growth only at high concentrations. Computational analysis showed that at least three receptor targets of Vx (5-HT₇, 5-HT_1D, and 5-HT_1B) were expressed at moderate/high levels in GBM. The 5-HT_1B receptor transcript was found in all GBM cell lines and was the only detectable Vx target in three of the five cell lines. Blocking 5-HT_1B with SB224289 abolished the anti-GBM effect of Vx, even in cells expressing other Vx. Conclusions: These findings demonstrate that therapeutic concentrations of Vx inhibit GBM cell proliferation and suggest that this action may be mediated, at least in part, by 5-HT_1B receptor activation.

MGlu5 metabotropic glutamate receptors are highly expressed and functional in early postnatal life, but their role in brain development remains to be elucidated. We now report that mGlu5^−/− mice showed a large reduction in mRNA and protein levels of myelin-associated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (MOG), and myelin basic protein (MBP) in the cerebral cortex and cerebellum at postnatal day (PND) 14. Expression of these proteins reflects oligodendrocyte differentiation and myelin formation in the CNS, a process that is prominent in the second week of postnatal life in mice. Expression of myelin markers recovered at later developmental stages, with the exception of MAG and MBP levels in the cerebellum, which were still reduced in mGlu5^−/− mice. We also observed a large reduction in myelin protein markers in the cerebral cortex and cerebellum of mice treated with the mGlu5 receptor negative allosteric modulator MTEP (3 mg/kg, i.p.) from PND 7 to PND 14. MTEP-treated mice also showed reduced motor coordination and sensorimotor function at PND 14. Treatment with MTEP reduced oligodendrocyte maturation without affecting proliferation of oligodendrocyte progenitor cells in primary cultures prepared from the rat cerebral cortex. These findings suggest that endogenous activation of mGlu5 receptors contributes to myelin formation during postnatal development in mice.