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BLOOD COMMENTARIES

PLENARY PAPER

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.

CLINICAL TRIALS AND OBSERVATIONS

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.

HEMATOPOIESIS AND 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.

LYMPHOID NEOPLASIA

Pararajalingam and colleagues performed large-scale genomic analysis for discovery and resequencing of 191 mantle cell lymphoma (MCL) samples with clinical follow-up, confirming the prognostic significance of TP53 and NOTCH1 mutations and revealing evidence for aberrant regulation of messenger RNA processing in MCL pathobiology.

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.

MYELOID NEOPLASIA

Lin and colleagues explored the issue of resistance to tyrosine kinase inhibition in chronic myeloid leukemia, implicating an important regulatory function of the microRNA miR-185, acting through PAK6, in determining the drug sensitivity of leukemic stem cells.

RED CELLS, IRON, AND ERYTHROPOIESIS

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.

TRANSPLANTATION

Deciding whether to recommend allogeneic transplantation for sickle cell disease is not straightforward. To assist, Brazauskas and colleagues propose a simple risk score comprising age and donor type based on their retrospective analyses of outcomes in 1425 patients.

VASCULAR BIOLOGY

Braun et al provide insights into a new regulatory pathway preventing vascular leakage during neutrophil diapedesis. Using murine models, they demonstrated that platelets prevent plasma leaks by binding to endothelium via VWF and releasing angiopoietin-1, which stimulates endothelial Tie-2 to trigger diapedesis pore closure.

LETTER TO BLOOD

BLOOD WORK

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