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Resistance to standard and novel therapies remains the main obstacle to cure in acute myeloid leukemia (AML) and is often driven by metabolic adaptations which are therapeutically actionable. Here we identify inhibition of mannose-6-phosphate isomerase (MPI), the first enzyme in the mannose metabolism pathway, as a sensitizer to both cytarabine and FLT3 inhibitors across multiple AML models. Mechanistically, we identify a connection between mannose metabolism and fatty acid metabolism, that is mediated via preferential activation of the ATF6 arm of the unfolded protein response (UPR). This in turn leads to cellular accumulation of polyunsaturated fatty acids, lipid peroxidation and ferroptotic cell death in AML cells. Our findings provide further support to the role of rewired metabolism in AML therapy resistance, unveil a novel connection between two apparently independent metabolic pathways and support further efforts to achieve eradication of therapy-resistant AML cells by sensitizing them to ferroptotic cell death.

Ritualized and repetitive behaviours are included in the diagnostic criteria for both autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD). OCD often co-occurs in young people with ASD, yet there is little clinical research on its phenomenology or treatment. The extant research in this area is largely composed of qualitative and single-subject study designs. In this chapter, we synthesize this body of research and provide recommendations for differential and dual diagnostic decision-making and treatment planning. The case of a 16-year-old male with comorbid ASD and OCD is presented, in which we demonstrate how standard cognitive-behavioural therapy (CBT) for OCD may be modified, for instance, to address problems with emotion regulation that hinder progression through an exposure-based therapy.