Concepts in B cell acute lymphoblastic leukemia pathogenesis.

B cell acute lymphoblastic leukemia (B-ALL) arises from genetic alterations impacting B cell progenitors, ultimately leading to clinically overt disease. Extensive collaborative efforts in basic and clinical research have significantly improved patient prognoses. Nevertheless, a subset of patients demonstrate resistance to conventional chemotherapeutic approaches and emerging immunotherapeutic interventions. This review highlights the mechanistic underpinnings governing B-ALL transformation. Beginning with exploring normative B cell lymphopoiesis, we delineate the influence of recurrent germline and somatic genetic aberrations on the perturbation of B cell progenitor differentiation and protumorigenic signaling, thereby facilitating the neoplastic transformation underlying B-ALL progression. Additionally, we highlight recent advances in the multifaceted landscape of B-ALL, encompassing metabolic reprogramming, microbiome influences, inflammation, and the discernible impact of socioeconomic and racial disparities on B-ALL transformation and patient survival.

Factor XII contributes to thrombotic complications and vaso-occlusion in sickle cell disease.

A hypercoagulable state, chronic inflammation, and increased risk of venous thrombosis and stroke are prominent features in patients with sickle cell disease (SCD). Coagulation factor XII (FXII) triggers activation of the contact system that is known to be involved in both thrombosis and inflammation, but not in physiological hemostasis. Therefore, we investigated whether FXII contributes to the prothrombotic and inflammatory complications associated with SCD. We found that when compared with healthy controls, patients with SCD exhibit increased circulating biomarkers of FXII activation that are associated with increased activation of the contact pathway. We also found that FXII, but not tissue factor, contributes to enhanced thrombin generation and systemic inflammation observed in sickle cell mice challenged with tumor necrosis factor α. In addition, FXII inhibition significantly reduced experimental venous thrombosis, congestion, and microvascular stasis in a mouse model of SCD. Moreover, inhibition of FXII attenuated brain damage and reduced neutrophil adhesion to the brain vasculature of sickle cell mice after ischemia/reperfusion induced by transient middle cerebral artery occlusion. Finally, we found higher FXII, urokinase plasminogen activator receptor, and αMß2 integrin expression in neutrophils of patients with SCD compared with healthy controls. Our data indicate that targeting FXII effectively reduces experimental thromboinflammation and vascular complications in a mouse model of SCD, suggesting that FXII inhibition may provide a safe approach for interference with inflammation, thrombotic complications, and vaso-occlusion in patients with SCD.