Issue Archive

von Willebrand factor (VWF) is a large multimeric plasma glycoprotein that plays well-established roles in hemostasis. Recent discoveries indicate that the importance of VWF transcends hemostasis and that there are many additional ligands for VWF beyond factor VIII, collagen, and platelet integrins. In this timely review, Atiq and O’Donnell put into perspective these recent findings, discussing how VWF also plays key roles in inflammation, wound healing, angiogenesis, and some nonhemostatic diseases.

Implementation barriers that diminish the potential benefits of highly effective therapies are common across the globe and may require concerted intervention to resolve. Koury et al describe the sustained improvement in outcomes for patients with acute promyelocytic leukemia in 5 Latin American countries from 2005-2020 due to the work of the International Consortium on Acute Leukemia. The authors report the long-term results from 806 patients in a prospective trial, identifying the key changes to practice that now enable outcomes for favorable-prognosis patients commensurate with those in high-income countries.

Escape from immune surveillance is a hallmark of symptomatic multiple myeloma (MM). Blanquart and colleagues compared bone marrow and peripheral blood natural killer (NK) cells from patients with MM and healthy donors. The authors reveal a contraction of CD56^dim cytotoxic subsets and expansion of late-stage “activated/inflammatory” CD16/CD226^Lo NK cells in MM. Leveraging different single-cell technologies, ex vivo studies, and clinical trial datasets, they demonstrate how NK cell dysfunction may negatively impact survival of patients with MM.

The pathogenesis of Waldenström macroglobulinemia (WM) is unknown. Chohan and colleagues report on multiomic comparative analyses (DNA methylation, whole exome, and RNA sequencing) of WM, IgM monoclonal gammopathy of undetermined significance (MGUS), and normal controls, identifying distinct patterns of transcriptional and epigenetic regulation associated with WM rather than MGUS. The authors’ data highlight the importance of epigenetic influence on cell signaling and inflammation-response pathways that differs between these entities.

Chronic granulomatous disease is a primary immunodeficiency disorder of phagocytes (neutrophils, eosinophils, monocytes/macrophages) due to inherited mutations in any of the genes encoding the protein components of the nicotinamide adenine dinucleotide phosphate reduced oxidase. Wolach et al report the outcomes of 110 patients with this rare disease that predisposes patients to recurrent infections and hyperinflammatory complications, identifying clear genotype-phenotype correlations and confirming the importance of allogeneic hematopoietic stem cell transplantation for those with severe disease.

Foxo1 is a transcription factor commonly associated with glucose metabolism. Xu et al reveal that Foxo1 also regulates the response of hepatocytes to high iron conditions and in iron overload by activation of hepcidin transcription. The authors’ data help explain how fluctuations in serum iron levels modulate the expression of hepcidin, a key iron-regulatory hormone that controls iron export from the gut and storage tissues.

Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome and carries a very high risk of myeloid neoplasm. While hematopoietic stem cell transplantation (HSCT) is curative, toxicity has limited its success because of the additional sensitivity of tissues to genotoxic conditioning and damage from graft-versus-host disease. In this month’s CME article, Lum and colleagues report that in the modern era, excellent outcomes can be expected for pediatric and adolescent patients with FA undergoing HSCT. These data support the use of HSCT from an HLA-matched family or unrelated donor as first-line treatment in patients with FA when cytopenia occurs and before the onset of clonal evolution.