ATG4A regulates human erythroid maturation and mitochondrial clearance
Although autophagy is essential for erythropoiesis, little is known about erythroid-specific mediators of this pathway. In this study, Stolla and colleagues identified a novel aspect of how autophagy regulates erythropoiesis that has not previously been appreciated. The authors used a genetic screen to pinpoint upregulation of ATG4A in maturing human erythroid cells. They subsequently depleted ATG4A in primary human hematopoietic stem and progenitor cells and found that it hindered erythroid differentiation, leading to reduced red cell production, delayed terminal differentiation, and impaired enucleation. The investigators also show that loss of ATG4A impaired autophagy and mitochondrial clearance, giving rise to reticulocytes with retained mitochondria and autophagic vesicles. These findings provide the first demonstration of ATG4A as a specific regulator of autophagy in erythroid development.
Using stroma-anchoring cytokines to augment ADCC: a phase 1 trial of F16IL2 and BI 836858 for posttransplant AML relapse
Natural killer (NK) cells are key effectors in cancer immunosurveillance and posttransplant immunity, but their efficiency is dependent on an optimal environmental milieu and proper tumor recognition. In this phase I trial, Berdel et al enrolled 15 patients with posttransplant acute myeloid leukemia (AML) relapse who were treated with 2 antibody constructs: 1 antibody targeting CD33, a validated target antigen in AML, the other antibody targeting the extracellular matrix (ECM) glycoprotein tenascin-C with IL-2 anchored to the construct. The authors found that the combination therapy stimulated the expansion and activation of NK cells, including those expressing the FcγRIIIA/CD16 receptor. These results indicate that ECM-targeted IL-2 combined with anti-CD33 immunotherapy may be an innovative approach for posttransplant AML relapse.
Transcutaneous ultrasound-mediated gene delivery into canine livers achieves therapeutic levels of factor VIII expression
Led by Manson et al, this is the first large animal study validating the use of nonviral DNA transfection that results in therapeutic clotting factor VIII levels in some dogs to above 10% for 2 months. This novel study may represent a potentially interesting alternative to AAV-FVIII gene therapy. Though transient transaminitis is still an issue with the current method (as is the case for most AAV-based trials utilizing high vector doses), the current approach could be applied to patients with hemophilia A, irrespective of their AAV seropositivity status. This would be a major advantage since currently only a fraction of patients with hemophilia A are AAV seronegative and qualify for AAV gene therapy.
Fertility testing knowledge and attitudes in male adolescents and young adults with SCD and their caregivers: a pilot study
Early diagnosis and improved therapies have resulted in more than 90% of youth with sickle cell disease (SCD) living into adulthood. These improvements, however, have been accompanied by diminished fertility in males that involves priapism, anemia, hypogonadism, and testicular infarction caused by the disease and/or antineoplastic treatments. As a result, semen abnormalities occur in males with SCD over their lifespans. In this study, Nahata and colleagues draw attention to the critical importance of providing fertility knowledge and counseling needs to young men with SCD. Despite most adolescents and young adults expressing a desire for biological parenthood, the authors found that male patients with SCD and their caregivers lack a good understanding of the importance of fertility status assessment by semen analysis.
Laboratory assays of VWF activity and use of desmopressin trials in the diagnosis of VWD: a systematic review and meta-analysis
This article by Kalot and colleagues summarizes the systematic reviews related to the diagnosis of von Willebrand disease (VWD) that contributed to the 2021 American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia guideline. This information is interesting and important in understanding the background of the recommendations made. As a follow up to the international guidelines on the diagnosis and management of VWD, this contribution is therefore an important addition to the field and addresses several questions that could not be covered in the guidelines, as well as providing guidance for future research.
Assessment of systemic and gastrointestinal tissue damage biomarkers for GVHD risk stratification
Etra et al report on a multicenter PRoBE study comparing various biomarker combinations for prediction of acute graft-versus-host disease (GVHD) outcomes, primarily 6-month NRM. They report that gastrointestinal tissue injury biomarker-based algorithms, specifically ST2 and REG3a, outperformed other combinations that include systemic inflammatory biomarkers.
