α-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia.

Perturbations in intermediary metabolism contribute to the pathogenesis of acute myeloid leukemia (AML) and can produce therapeutically actionable dependencies. Here, we probed whether alpha-ketoglutarate (aKG) metabolism represents a specific vulnerability in AML. Using functional genomics, metabolomics, and mouse models, we identified the aKG dehydrogenase complex, which catalyzes the conversion of aKG to succinyl CoA, as a molecular dependency across multiple models of adverse-risk AML.

Position statement on the diagnosis and management of acute leukaemia and aggressive lymphomas in pregnancy.

Haematological malignancies affect 12·5 in 100 000 pregnancies. Over the past two decades, the number of haematological malignancies in pregnancy has substantially increased. Life-threatening haematological malignancies in pregnancy, such as acute leukaemia and aggressive lymphomas, pose a unique therapeutic challenge: clinicians must consider both maternal and fetal wellbeing, aiming to deliver optimal curative therapy for the patient and a successful pregnancy outcome.

Discovery and clinical translation of ceperognastat, an O-GlcNAcase (OGA) inhibitor, for the treatment of Alzheimer's disease.

Introduction: The aggregation and spread of hyperphosphorylated, pathological tau in the human brain is hypothesized to play a key role in Alzheimer's disease (AD) as well as other neurogenerative tauopathies. O-GlcNAcylation, an important post-translational modification of tau and many other proteins, is significantly decreased in brain tissue of AD patients relative to healthy controls. Increased tau O-GlcNAcylation has been shown to reduce tau pathology in mouse in vivo tauopathy models.

Interferon-ε loss is elusive 9p21 link to immune-cold tumors, resistant to immune-checkpoint therapy and endogenous CXCL9/10 induction.

Introduction: Copy-number (CN) loss of chromosome 9p, or parts thereof, impair immune response and confer ICT resistance by direct elimination of immune-regulatory genes on this arm, notably IFNγ genes at 9p24.1, and type-I interferon (IFN-I) genes at 9p21.3.