Issue Archive

Diamond-Blackfan anemia (DBA) is typically caused by mutations in ribosomal protein (RP) genes leading to impaired erythroid development; however, in about 25% of cases, the cause is unknown. In this Plenary Paper, O’Donohue and colleagues identify biallelic mutations in HEATR3, a gene of previously uncertain function in humans, in 4 unrelated families with DBA. A series of elegant studies reveal that HEATR3 is important for RP import into the nucleus and that deficiency of HEATR3 causes defects in ribosomal biogenesis.

Using a series of 5 illustrative cases, Berman updates current approaches to the treatment of chronic-phase chronic myeloid leukemia (CML) in the context of the continued development of second and third generation tyrosine kinase inhibitors. She discusses the approach to patients who did not respond adequately to first-line therapy, the new agents bosutinib and asciminib, the approach to family planning for women with CML, and the milestones for treatment cessation.

Treatment of mantle cell lymphoma (MCL) continues to improve. Song et al present longer term outcomes of a phase 2 study of zanubrutinib therapy for 86 patients with relapsed/refractory MCL. Outcomes were promising, with an overall response of 83.7%, a complete response rate of 77.9%, and no new safety concerns. At 36 months, this translates to an estimated progression-free survival of 47.6% and overall survival of 74.8%.

Individuals with Down syndrome have a predisposition to acute megakaryoblastic leukemia (AMKL) associated with GATA1 mutations that generate a short GATA1 isoform (GATA1s). Hasle et al describe 2 families with germline GATA1s-generating mutations in which several family members developed AMKL that mimics those seen in patients with Down syndrome, including acquisition of trisomy 21. This finding suggests that trisomy 21 and GATA1 mutation combine to induce a unique subtype of myeloid leukemia regardless of which mutation is the primary event.

Neutrophils are critical to the innate immune response, and one mechanism for eliminating pathogens is their ability to release neutrophil extracellular traps (NETs). Sprenkeler and colleagues demonstrated that actin polymerization is required for NET formation, perhaps by facilitating translocation of neutrophil elastase to the nucleus.

Anemia of inflammation (AI) is associated with both hepcidin-induced disruption of iron trafficking and erythropoietin (EPO) resistance. Dulmovitz and colleages elucidated a novel mechanism of EPO resistance in AI. They show that high mobility group box 1 protein (HMGB1), a damage-associated molecular pattern molecule increased in AI, reduces expansion and increases apoptosis of EPO-sensitive precursors by interfering with EPO binding to its receptor and decreasing EPO signaling.

Platelets are known to contribute to arterial thrombosis and have been hypothesized to also play a role in venous thrombosis (VT). Mwiza and colleagues studied the role of platelets in VT and demonstrated that platelet activation is required for VT in mice. Thrombosis is decreased by combining aspirin and clopidogrel together, suggesting that signaling through G protein–coupled receptors and immunoreceptor tyrosine-based activation motif receptors is required for clot formation.