Ticagrelor in pediatric sickle cell disease, UBA1 translation impacts severity of VEXAS syndrome, and T-cell immunity and chemotherapy response in ALL
In this week’s episode we’ll learn more about the negative findings from the phase three trial of ticagrelor for preventing vaso-occlusive crises in children with sickle cell disease, discuss how residual cytoplasmic UBA1 contributes to the pathogenesis of VEXAS syndrome, and learn more about the impact of host T-cell immunity in the response to chemotherapy in pediatric ALL.
Ticagrelor vs placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: the HESTIA3 study
Platelets play a role in sickle cell disease (SCD)-related thromboinflammation through platelet-platelet and platelet-neutrophil interactions. Heeney et al report on results from a phase 3 international trial studying efficacy and safety of the P2Y12 (ADP receptor) inhibitor ticagrelor vs placebo for the prevention of SCD crises. Despite successful inhibition of platelet activation, ticagrelor did not decrease the frequency of vaso-occlusive crisis, underscoring the complexity of factors contributing to SCD-related vaso-occlusion.
Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis
The adult-onset inflammatory disease termed VEXAS (vacuoles, E1 ubiquitin activating enzyme, X-linked, autoinflammatory, and somatic) syndrome is caused by mutations in UBA1. VEXAS syndrome has high mortality, but the clinical course is heterogeneous. Ferrada and colleagues demonstrate that the heterogeneity is associated with the specific mutations in UBA1 and correlates with the degree of residual expression of the normal UBA1b cytoplasmic isoform of UBA1.
Impact of T-cell immunity on chemotherapy response in childhood acute lymphoblastic leukemia
Li et al address the role of T-cell immunity on Ph+ acute lymphoblastic leukemia (ALL) outcomes. Using a mouse model, they show that T cells are necessary to maintain response to either tyrosine kinase inhibition or cytotoxic chemotherapy. The authors correlate this with the observation that peripheral blood T-cell abundance in 102 children with ALL was associated with treatment outcomes.
The Gab2–MALT1 axis regulates thromboinflammation and deep vein thrombosis
Kondreddy and colleagues elucidate an endothelial pathway regulating deep vein thrombosis related to thromboinflammation. They report that a signaling adapter protein, Gab2, propagates signaling from inflammatory mediators in endothelial cells. Inhibition of the Gab2 pathway decreases leukocyte accumulation and attenuates venous thrombosis at sites of injury in mice, suggesting that targeting this pathway can inhibit thrombosis without inhibiting coagulation.
CAR T-cell therapy in highly aggressive B-cell lymphoma: emerging biological and clinical insights
CAR T-cell therapy targeting CD19 has proven highly effective in patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL), and several products have received approval. Ali et al review the role of this approach for other high-grade non-DLBCL B-cell lymphomas. They discuss how improved understanding of the biological features of these distinct lymphoma subtypes and further testing are needed to define the role of CAR T-cell therapy in their management.
