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BLOOD COMMENTARIES

PERSPECTIVE

Lansdorp contributes a personal perspective that reviews the literature around telomeres and aging and proposes a model that synthesizes data from mice and humans in conjunction with evolutionary theory. Differences in average telomere length between humans and between cell types help explain differences in the risk of developing cancer and other age-related diseases. These ideas are captured in the “telomere erosion in disposable soma” theory of aging proposed here.

REVIEW ARTICLE

Approximately one-fourth of all patients diagnosed with diffuse large B-cell lymphoma (DLBCL) have localized (or limited-stage) disease. Hawkes et al provide a comprehensive review of biological characteristics and treatment options for these patients, including those being managed in resource-constrained areas where access to positron emission scanning is not possible.

CLINICAL TRIALS AND OBSERVATIONS

Cavo et al confirmed the prognostic value of uniformly conducted prospective minimal residual disease (MRD) assessments with next-generation sequencing in multiple myeloma (MM) through a robust analysis of pooled data of 2510 patients from 4 recent phase 3 registrational studies. This report is timely, as MRD negativity using highly sensitive assays is being explored as a potential surrogate endpoint in clinical trials to accelerate drug approval and to guide future treatment strategies for MM.

HEMATOPOIESIS AND STEM CELLS

Histone acetylation acts to unfold chromatin to facilitate DNA access for replication or transcription. By analyzing two mouse models, Yang and colleagues revealed the importance of HBO1, an enzyme that establishes acetylation of histone 3 lysine 14, to maintenance of the blood system. They established that HBO1 promotes hematopoietic stem cell (HSC) quiescence and self-renewal, thereby protecting against HSC exhaustion. This study provides data that could inspire the development of new epigenetic modulators for therapeutic purposes.

LYMPHOID NEOPLASIA

Johnston et al demonstrate differences in gene expression between pediatric and adult classical Hodgkin lymphoma (cHL), finding that eosinophil, B-cell, and mast cell signatures were enriched in children while macrophage and stromal cell signatures were more prominent in adults. They also developed and validated a gene expression profile–based model reflective of the tumor microenvironment biology, but independent of clinical features, that predicts event-free survival in pediatric patients. This model may be applicable for use in future clinical trials.

MYELOID NEOPLASIA

Mutant RUNX1 (mtRUNX1), either somatic or germline, is associated with poor prognosis in acute myeloid leukemia (AML). Mill and colleagues used cell line and murine models to document that mtRUNX1 AMLs exhibit impaired ribosomal biogenesis and increased sensitivity to protein translation inhibitors, such as omacetaxine. Omacetaxine represses c-MYC, MCL1, and BCL-xL and is additive when combined either with the BCL2 inhibitor venetoclax or with BET inhibitors, suggesting a strategy for future clinical evaluation.

PLATELETS AND THROMBOPOIESIS

Platelet α-granules are lysosome-related organelles loaded with hundreds of proteins that are either synthesized by megakaryocytes or internalized via endocytosis. Ambrosio et al identified 3 proteins and complexes that contribute to platelet α-granule biogenesis. Their work greatly advances knowledge into how cargos are packaged and how megakaryocytes repurpose the ubiquitous endosome retrieval and recycling machinery for trafficking of α-granule proteins.

RED CELLS, IRON, AND ERYTHROPOIESIS

Using a murine model of sickle cell disease (SCD), Menon et al show that excess circulating free heme upregulates cardiac heme oxygenase 1, resulting in increased cardiac nonheme iron and lipid peroxidation leading to ferroptosis and impaired cardiac function. These findings reveal an important mechanism underlying cardiac complications in SCD and provide the potential for novel interventional approaches for cardioprotection in patients with SCD.

LETTERS TO BLOOD

BLOOD WORK

ERRATUM

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