Issue Archive

In this Blood Spotlight review, Thompson and Tam discuss the emerging preclinical and clinical data on pirtobrutinib in B-cell lymphoproliferative diseases, particularly mantle cell lymphoma. The authors highlight key insights related to its pharmacological features and provide perspective on its suitability for applications in combinations and in other diseases.

Testing for genetic abnormalities that inform diagnosis, prognosis, and treatment selection for many hematological diseases is rapidly increasing. Inevitably, hematologists will be frequently faced with results showing or suggesting germ line genetic abnormalities, both expected and unexpected. Hamilton and colleagues use 3 illustrative cases from acute leukemia and allogeneic transplant settings to explain key concepts that underpin best practice in how this information should be communicated.

Approved chimeric antigen receptor (CAR) T cells incorporate the intracellular signaling domains of either costimulatory molecules CD28 or 41BB to enhance persistence and function, but chronic continuous stimulation of T cells can cause dysfunction. Selli et al reveal that with chronic antigen stimulation, CD28-bearing CAR T cells demonstrate the cellular and biochemical hallmarks of classic T-cell exhaustion, while 41BB-bearing CAR T cells display a distinct signature with reactivation of the transcription factor, FOXO3. Suppression of FOXO3 improves CAR T-cell function, suggesting new avenues for maintaining CAR T-cell efficacy.

Exploiting the power of multiple high throughput omic analyses, Largeot and colleagues describe the consequences for human and murine chronic lymphocytic leukemia (CLL) when protein translation initiation is inhibited. These insights suggest potential strategies to indirectly target MYC-driven proliferation for treatment of aggressive CLL.

Interleukin (IL)-34 is produced by osteoclasts and is important in innate immunity. Xie et al discovered a novel role of this cytokine in promoting hematopoietic progenitor and acute myeloid leukemia (AML) differentiation by binding to triggering receptor expressed on myeloid cells 2 (TREM2), a previously unrecognized receptor for IL-34. Using preclinical models and human samples, the authors elucidate the signaling pathway and provide preliminary data supporting exploration of IL-34 to address differentiation blockade in AML.

It is well established that iron deficiency alters the polycythemia vera (PV) phenotype, but whether regulation of iron homeostasis modulates the pathophysiology of JAK2 V617F PV has been unclear. Bennett and colleagues use unbiased genome-wide analyses to establish and validate an association between disordered iron homeostasis and PV diagnosis. The authors then go on to show how hepcidin levels govern the severity of the erythroid phenotype in a murine model of PV. These data may inform future use of emerging drugs that mimic hepcidin action.

Factor V (fV) plays multiple roles in hemostasis. In the east Texas bleeding disorder, a short splice variant of fV is abundant and aberrantly binds tissue factor pathway inhibitor, thereby indirectly perturbing prothrombinase and procoagulant activity. Mohammed et al report on a complete atomic-resolution structure of fV short, providing molecular context and valuable clues to understanding the unique functional properties of fV short.