HemaSphere最新文献

Hemochromatosis is an inherited iron overload condition caused by mutations that reduce the levels of the iron-regulatory hormone hepcidin or its binding to ferroportin. The hepcidin–ferroportin axis is pivotal to iron homeostasis, providing opportunities for therapeutic intervention in iron overload disorders like hemochromatosis. The aim of this study was to evaluate the efficacy of the oral ferroportin inhibitor vamifeport in the Hfe C282Y mouse model, which carries the most common mutation found in patients with hemochromatosis. A single oral dose of vamifeport lowered serum iron levels in Hfe C282Y mice, with delayed onset and shorter duration than observed in wild-type mice. Vamifeport induced transient hypoferremia by inhibiting ferroportin and resulted in a feedback regulation of liver Hamp in wild-type mice, which was absent in Hfe C282Y mice, reflecting the dysregulated systemic iron sensing in this hemochromatosis model. Chronic dosing with vamifeport led to sustained serum and liver iron reductions in Hfe C282Y mice, as well as markedly reducing liver Hamp expression in Hfe C282Y mice, suggesting distinct regulation of liver Hamp expression following acute or continuous iron restriction via vamifeport. At the tested dose, vamifeport retained its activity when combined with phlebotomy and did not significantly interfere with liver iron removal by phlebotomy in Hfe C282Y mice. These data demonstrate that chronic vamifeport treatment significantly reduces serum iron levels and prevents liver iron loading in the Hfe C282Y mouse model of hemochromatosis, thus providing preclinical proof of concept for the efficacy of vamifeport in hemochromatosis with or without phlebotomy.

Pediatric classic Hodgkin lymphoma (cHL) patients have a high survival rate but suffer from severe long-term side effects induced by chemo- and radiotherapy. cHL tumors are characterized by the low fraction (0.1%–10%) of malignant Hodgkin and Reed–Sternberg (HRS) cells in the tumor. The HRS cells depend on the surrounding immune cells for survival and growth. This dependence is leveraged by current treatments that target the PD-1/PD-L1 axis in cHL tumors. The development of more targeted therapies that are specific for the tumor and are therefore less toxic for healthy tissue compared with conventional chemotherapy could improve the quality of life of pediatric cHL survivors. Here, we applied single-cell RNA sequencing (scRNA-seq) on isolated HRS cells and the immune cells from the same cHL tumors. Besides TNFRSF8 (CD30), we identified other genes of cell surface proteins that are consistently overexpressed in HRS cells, such as NRXN3 and LRP8, which can potentially be used as alternative targets for antibody–drug conjugates or CAR T cells. Finally, we identified potential interactions by which HRS cells inhibit T cells, among which are the galectin-1/CD69 and HLA-II/LAG3 interactions. RNAscope was used to validate the enrichment of CD69 and LAG3 expression on T cells near HRS cells and indicated large variability of the interaction strength with the corresponding ligands between patients and between tumor tissue regions. In conclusion, this study identifies new potential therapeutic targets for cHL and highlights the importance of studying heterogeneity when identifying therapy targets, specifically those that target tumor-immune cell interactions.

Immune dysregulation is a hallmark of chronic lymphocytic leukemia (CLL). Anti-CD20 antibodies (e.g., rituximab [R]) can be combined with venetoclax (Ven) to treat CLL. However, anti-CD20 antibodies can increase hypogammaglobulinemia risk, while the effects of Ven on immune dysregulation are still uncertain. We report long-term immune changes in VenR- and bendamustine-R (BR)-treated patients with relapsed/refractory CLL in the MURANO trial (NCT02005471). Patients were randomized to fixed-duration VenR (2 years Ven; VenR for the first 6 months) or BR (6 months). Immune cell levels were evaluated at the end of combination treatment (EOCT), end of treatment (EOT; VenR arm only), and 12 and 24 months post-EOCT. Overall, 130/194 VenR- and 134/195 BR-treated patients completed treatment without progressive disease. In patients who completed VenR combination therapy, median immunoglobulin (Ig)G and IgM levels decreased from baseline to EOT (p ≤ 0.01 and p ≤ 0.0001, respectively); by 24 months, post-EOT IgG had returned to baseline level and IgM had increased from baseline (p ≤ 0.001). Median IgA levels increased from baseline to 12 (p ≤ 0.0001) and 24 months post-EOT (p ≤ 0.0001). In BR-treated patients, changes in IgG, IgA, and IgM levels across the assessed time points were not significant, and by 24 months, post-EOCT IgG, IgA, and IgM were above baseline levels. Grade ≥3 infection rates on treatment were low. Overall, immune recovery was observed with VenR and BR, with stabilization of Ig levels after treatment. Post-treatment infection rates were generally low, making these very tolerable therapies for CLL.

Strict control over hematopoietic stem cell decision making is essential for healthy life-long blood production and underpins the origins of hematopoietic diseases. Acute myeloid leukemia (AML) in particular is a devastating hematopoietic malignancy that arises from the clonal evolution of disease-initiating primitive cells which acquire compounding genetic changes over time and culminate in the generation of leukemic stem cells (LSCs). Understanding the molecular underpinnings of these driver cells throughout their development will be instrumental in the interception of leukemia, the enabling of effective treatment of pre-leukemic conditions, as well as the development of strategies to target frank AML disease. To this point, a number of precancerous myeloid disorders and age-related alterations are proving as instructive models to gain insights into the initiation of LSCs. Here, we explore this myeloid dysregulation at the level of post–transcriptional control, where RNA-binding proteins (RBPs) function as core effectors. Through regulating the interplay of a myriad of RNA metabolic processes, RBPs orchestrate transcript fates to govern gene expression in health and disease. We describe the expanding appreciation of the role of RBPs and their post–transcriptional networks in sustaining healthy hematopoiesis and their dysregulation in the pathogenesis of clonal myeloid disorders and AML, with a particular emphasis on findings described in human stem cells. Lastly, we discuss key breakthroughs that highlight RBPs and post–transcriptional control as actionable targets for precision therapy of AML.

CD19-directed autologous chimeric antigen receptor T cell (CAR-T) therapy has transformed the management of relapsed/refractory (R/R) large B cell lymphoma (LBCL). Initially approved in the third line and beyond setting, CAR-T is now standard of care (SOC) for second-line treatment in patients with refractory disease or early relapse (progression within 12 months) following primary chemoimmunotherapy. Despite becoming SOC, most patients do not achieve complete response, and long-term cure is only observed in approximately 40% of patients. Accordingly, there is an urgent need to better understand the mechanisms of treatment failure and to identify patients that are unlikely to benefit from SOC CAR-T. The field needs robust biomarkers to predict treatment outcome, as better understanding of prognostic factors and mechanisms of resistance can inform on the design of novel treatment approaches for patients predicted to respond poorly to SOC CAR-T. This review aims to provide a comprehensive overview of clinical, molecular, imaging, and cellular features that have been shown to influence outcomes of CAR-T therapy in patients with R/R LBCL.