Validation and clinical application of transactivation assays for RUNX1 variant classification
This Stimulus Report by Decker et al highlights the challenges interpreting the pathogenicity of RUNX1 variants and limitations of the current ACMG/ClinGen criteria leading to the classification of “variants of uncertain significance.” The luciferase reporter assays (previously described by the team) were able to determine likely pathogenicity in 2 out of 11 variants tested against specific criteria, while in other families, functionality of variants was demonstrated consistent with clinical phenotypes. This article discusses the validation and clinical application of these tests as well as the advantages and limitations of implementing luciferase reporter transactivation assays within clinical testing and defines how these tests may practically be integrated into clinical pathways to support patient care.
SAXS analysis of the intrinsic tenase complex bound to a lipid nanodisc highlights intermolecular contacts between factors VIIIa/IXa
Led by Childers and colleagues, this study uses a combination of SAXS analysis and modeling to investigate how factor VIIIa associates with factor IXa on membrane surfaces. These studies are bolstered by insights from known mutations in these proteins from patients with hemophilia. Overall, the study provides new insights into the assembly and function of this important protein complex.
Clinical activity of single-dose systemic oncolytic VSV virotherapy in patients with relapsed refractory T-cell lymphoma
Clinical successes attributed to intravenous (IV) oncolytic virotherapy (OV) has largely been anecdotal. Cook et al conducted a phase 1 clinical trial of systemic OV therapy and investigated the mechanisms of action in responding patients with T-cell lymphoma (TCL). Although the numbers of subjects were small, the authors found that a single IV dose of VSV-IFNβ-NIS was safe and effective in patients with TCL as evidenced by durable disease remissions in heavily pretreated patients. This article is one of the first to demonstrate the therapeutic benefit of a replicating oncolytic virus following a single IV dose in diverse leukemic patients, opening the door for further clinical testing.
Identification of novel γ-globin inducers among all potential erythroid druggable targets
Reactivation of human γ-globin genes in adult red blood cells (RBC) can ameliorate symptoms associated with inherited β-globinopathies, sickle cell disease (SCD), and other RBC disorders. Nonetheless, genetic reactivation strategies face significant global implementation barriers, limiting their worldwide utility. Pharmacological induction of γ-globin synthesis, however, may provide treatment avenues for a greater number of affected individuals. In this study, Engel and colleagues generated a CRISPR knockout library to screen for novel inducers of fetal hemoglobin...
Blocking human protein C anticoagulant activity improves clotting defects of hemophilia mice expressing human protein C
Current factor replacement therapies for hemophilia A and B have limitations necessitating the need for alternative treatment strategies. In this study, Jiang and colleagues examined the therapeutic potential of monoclonal antibody HAPC1573, which selectively blocks the anticoagulant activity of human activated protein C (APC). To test the potential of HAPC1573, the team generated F8-/- or F9-/- hemophilia mice that replaced murine protein C (Proc) with the human PROC gene. The investigators found that HAPC1573 pretreatment resulted in shortened tail bleeding time, reduced mortality, and dampened joint swelling.
Deep sequencing in CD34+ cells from peripheral blood enables sensitive detection of measurable residual disease in AML
Stasik et al report on the development of a novel measurable residual disease technique for CD34+ acute myeloid leukemia (AML) combining flow- or magnetic-based selection of peripheral blood CD34+ cells coupled with error-corrected next-generation sequencing. By investigating serial blood samples from 30 patients with AML monitored post-HSCT in the RELAZA trial, they demonstrate that their technique can increase the detection of mutant alleles in peripheral blood 1000-fold. Further, they can anticipate molecular relapse by a median of 6 weeks compared to their previous method, based on donor chimerism of sorted CD34+ cells.
