Issue Archive

Fibrin clots form through thrombin-mediated conversion of fibrinogen into monomeric fibrin, which then polymerizes. Lack of fibrinogen leads to severe bleeding, lack of platelet aggregation, and delayed wound healing. However, in this Plenary Paper, Hur and colleagues show that fibrin polymerization is not required for these functions in vivo in mice expressing nonpolymerizable fibrinogen. Further, these mice were protected against venous thrombosis and had suppressed arterial thrombosis, revealing new avenues to reducing thrombosis without increasing bleeding.

Emergence of CD19-negative disease and limited chimeric antigen receptor (CAR) T-cell persistence have emerged as the major limitations of current CD19 CAR T-cell approaches for pediatric relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). In a phase 1 clinical trial investigating a novel CD19/CD22-bispecific CAR T-cell product, Ghorashian et al report no antigen-negative relapses among a cohort of 12 patients with relapsed ALL. Although requiring more mature follow-up and confirmation in larger studies, these data suggest progress toward reducing a major mechanism of treatment failure.

Hematopoietic stem cells (HSCs) alter their function during aging. B. Tang and colleagues newly identify the RNA-binding protein FUS as an effector of HSC aging, with its protein levels increasing in HSCs with age and aberrant FUS condensates forming. These aberrant FUS condensates induce a global 3-dimensional chromatin reorganization by blurring the boundaries of topology-associating domains, and this generates an aged HSC-like transcriptional signature.

Chimeric antigen receptor (CAR) T-cell therapies hold promise for the treatment of multiple myeloma, but expression of immune checkpoints such as CD200 by malignant plasma cells often drives CAR T-cell exhaustion. Y. Tang and colleagues engineered several CAR constructs to explore how to best overcome this barrier to successful therapy. By utilizing the CD200 expression to drive CD28 costimulation of their B-cell maturation antigen–targeting CAR T cells, the authors demonstrate promising in vitro and in vivo activity in preclinical models. Such an approach requires testing in clinical trials.

Plasmablastic lymphoma is a rare and aggressive form of large B-cell lymphoma that has been associated with immunodeficiency and poor prognosis in small case series. Di Ciaccio et al more completely define this entity, reporting on a multinational series of 281 patients that confirms the strong association with immunodeficiency. While response rates exceeded 70%, outcomes were poor despite intensive regimens, with Epstein-Barr virus–negative lymphoma, poor performance status, and advanced stage being negative prognostic features. New therapeutic strategies, especially for the highest risk forms, are clearly needed.

Inhibitor of DNA-binding 3 (Id3) is a helix-loop-helix transcription factor that plays a key role in T-cell biology, being involved in both T-cell development and emergence of T-cell memory. Wang and colleagues report that genetic ablation of Id3 attenuates graft-versus-host disease (GVHD) through upregulation of PD-1 expression in alloreactive donor T cells but does not diminish antileukemic activity in murine transplant models. This work suggests that targeting Id3 may provide a new avenue for GVHD prevention and treatment.