In this week's episode we will review a study that demonstrates how the impaired hematopoietic stem cells (HSCs) observed in β-thalassemia can be rescued by administration of parathyroid hormone, learn more about genetic variants that can increase the risk of venous thromboembolism, and explore the identification of two DNA methylation subtypes of Waldenström’s macroglobulinemia.
Functional and genetic testing in adults with HLH reveals an inflammatory profile rather than a cytotoxicity defect
While primary hemophagocytic lymphohistiocytosis (HLH) is explained by genetic deficiencies in lymphocyte cytotoxicity, the role of intrinsic cytotoxicity defects in the more common secondary HLH has not been defined. Carvelli and colleagues reveal that no major intrinsic cytotoxicity dysfunction is seen in secondary HLH when appropriate comparisons are made with patients having the same precipitating diseases but without HLH.
MDH1-mediated malate-aspartate NADH shuttle maintains the activity levels of fetal liver hematopoietic stem cells
Gu et al used a transgenic mouse model that reports mitochondrial respiration to explore how energy metabolism and stemness interrelate between different stages of developmental hematopoiesis. Their work reveals that fetal liver stem cells principally use mitochondrial respiration as their main energy source and demonstrates how this is tightly regulated.
Identification of 2 DNA methylation subtypes of Waldenström macroglobulinemia with plasma and memory B-cell features
The B cells of 35 patients with MYD88-mutated Waldenström macroglobulinemia (WM) were studied by Roos-Weil et al, using integrated genome-wide DNA methylation, transcriptome, and mutation profiling. Their data suggest that WM can be subdivided into 2 major groups (memory B-cell–like and plasma cell–like) based on patterns of DNA methylation, each associating with different genetic and phenotypic features.
Hematopoietic stem cell function in β-thalassemia is impaired and is rescued by targeting the bone marrow niche
Aprile et al report bone marrow niche defects in a well-established murine model of β-thalassemia and suggest that the niche renders stem cells more proliferative due to reduced parathormone (PTH) expression and impaired osteolineage niche regulation. Importantly, the stem cell defect can be corrected by PTH treatment, suggesting possibilities for targeting this niche in clinical care.
Whole-exome sequencing identifies rare variants in STAB2 associated with venous thromboembolic disease
In this Plenary Paper, Desch and colleagues describe whole-exome sequencing of patients with venous thromboembolic disease (VTE) vs controls and novel analytic techniques to identify rare STAB2 variants associated with VTE, each of which reduces the surface expression of the gene product stabilin-2. Stabilin-2 enhances clearance of von Willebrand factor (VWF), and elevated levels of VWF are observed in patients with STAB2 variants, suggesting a mechanism for the elevated VTE risk. This work establishes STAB2 as a thrombophilia gene.