Blood Podcast: Season 1, Episode 32
In this week’s episode we will review a study exploring the use of a novel hemophilia A mouse model to examine emicizumab function in vivo, a new approach to fighting the cytokine storm of HLH with a combination of glucocorticoids and ruxolitinib, and a timely Letter to Blood about red cell-bound antibodies and transfusion requirements in hospitalized patients with COVID-19.
JAK/STAT pathway inhibition sensitizes CD8 T cells to dexamethasone-induced apoptosis in hyperinflammation
In a Plenary Paper, the authors demonstrate that cytokine-induced JAK/STAT signaling mediates cell resistance to dexamethasone and that glucocorticoid-induced apoptosis can be reestablished with the JAK inhibitor ruxolitinib. This suggests that dexamethasone plus ruxolitinib is a potent combination for treating hemophagocytic lymphohistiocytosis (HLH) and other cytokine storm–related syndromes.
LUBAC accelerates B-cell lymphomagenesis by conferring resistance to genotoxic stress on B cells
Diffuse large B-cell lymphoma of the activated B-cell type (ABC-DLBCL) often overexpresses linear ubiquitin chain assembly complex (LUBAC). Jo et al studied a mouse model of LUBAC overexpression, demonstrating that LUBAC cooperates with MYD88 to promote lymphomagenesis and can be targeted by a LUBAC-specific inhibitor. Since MYD88-mutated ABC-DLBCL often overexpresses LUBAC, this study suggests a potential new approach to therapy for these poor-prognosis lymphomas.
Human erythroleukemia genetics and transcriptomes identify master transcription factors as functional disease drivers
Fagnan et al studied the genetic landscape of acute erythroleukemia (AEL) in a cohort of 33 patient samples. Transcriptomics confirm that these leukemias segregate into 3 subgroups. The authors discerned a shared AEL-specific pattern of aberrant expression of regulators of erythroid differentiation converging on repression of GATA1 activity.
Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis
Yu et al dissected the complex role of transferrin in maintaining iron homeostasis. In elegant mouse studies, they demonstrated that transferrin, which is synthesized primarily in the liver, is important in blocking hepatic iron accumulation. Liver-specific transferrin knockout mice develop severe iron overload and hepatic fibrosis that can be blocked by deleting a second iron transporter, Slc39a14.
A hemophilia A mouse model for the in vivo assessment of emicizumab function
The bispecific antibody emicizumab bridges factor IXa and factor X, effectively replacing the function of factor VIII in hemophilia A, but measurement of factor VIII activity is inaccurate in the presence of the drug. Using a novel approach in a hemophilia mouse model, Ferrière et al confirmed that emicizumab generates a factor VIII activity equivalent to about 9% and that small doses of factor VIII greatly enhance its efficacy against bleeding, providing a platform for optimizing therapy.
