Issue Archive

Introduced by Associate Editor Thomas Ortel, this Review Series focuses on factor XI (FXI). The series opens with a review of the biology of FXI, proceeds to a discussion of congenital FXI deficiency, and concludes with a discussion of the use of therapies targeting FXI and factor XIa as active anticoagulants with a decreased risk of bleeding complications.

Introduced by Associate Editor Thomas Ortel, this Review Series focuses on factor XI (FXI). The series opens with a review of the biology of FXI, proceeds to a discussion of congenital FXI deficiency, and concludes with a discussion of the use of therapies targeting FXI and factor XIa as active anticoagulants with a decreased risk of bleeding complications.

Introduced by Associate Editor Thomas Ortel, this Review Series focuses on factor XI (FXI). The series opens with a review of the biology of FXI, proceeds to a discussion of congenital FXI deficiency, and concludes with a discussion of the use of therapies targeting FXI and factor XIa as active anticoagulants with a decreased risk of bleeding complications.

Introduced by Associate Editor Thomas Ortel, this Review Series focuses on factor XI (FXI). The series opens with a review of the biology of FXI, proceeds to a discussion of congenital FXI deficiency, and concludes with a discussion of the use of therapies targeting FXI and factor XIa as active anticoagulants with a decreased risk of bleeding complications.

The small Rho-family guanosine triphosphate hydrolase RAC2 functions mainly in immune cells, and RAC2 mutations lead to immune deficiency ranging from severe combined immunodeficiency (SCID), infantile neutrophilic disorder (IND), and later-onset combined immune deficiency (CID). Donkó et al examined the spectrum of RAC2-related syndromes in 54 patients from 37 families and performed functional analysis of mutations to explain the variable phenotypes. The authors found that constitutively active mutations cause SCID, dominant-negative mutations cause IND, and dominant-activating mutations cause CID. This careful linking of the range of RAC2 activity offers the potential for better diagnosis, therapy, and future research.

Immunotherapy of acute myeloid leukemia (AML) with γδ T cells is being promoted because γδ T cells are not HLA-restricted and do not represent antigen via presentation by HLA, making them excellent candidates for off-the-shelf immunotherapy. Mensurado et al set out to elucidate AML cell recognition by Vδ1⁺ T cells (Delta One T [DOT] cells). The authors identified CD155/pulmonary vascular resistance (PVR) as the major protein allowing activation of DOT cells, suggesting that PVR expression may predict success of immunotherapy with DOT cells.

Patients with Sézary syndrome (SS) are prone to Staphylococcus aureus infections and have treatment resistance which leads to poor prognosis. Vadivel and colleagues link these observations, suggesting that staphylococcal enterotoxins (SE) induce drug resistance in SS T cells through induction of several T-cell signaling pathways. Treatment with antibacterials as well as downstream mediators triggered by SE abrogate drug resistance, suggesting that antistaphylococcal antibiotics might improve outcomes of SS-directed therapy.

Bourgeois and colleagues report that in combination, the potent IKAROS protein degrader mezigdomide and menin inhibitors demonstrate synergistic activity against lysine methyltransferase 2A (KMT2A)–rearranged and nucleophosmin-mutant (NPM1c) acute myeloid leukemia (AML). Mezigdomide also has single-agent activity in AML cells and xenografts. These data support clinical trials of this novel combination in KMT2A-rearranged and NPM1c-mutant AML.

Yang et al investigated the genetic basis for gestational thrombocytopenia (GT). Using sequencing data from over 100 000 individuals, the authors determined variants in PEAR1 and TUBB1 as important contributors to an accelerated decrease in platelet counts in pregnancy and elevated risk of GT.

Jak2^V617F (Jak2^VF) is a major driver of BCR::ABL-negative myeloproliferative neoplasms but is also a common mutation in clonal hematopoiesis (CH). Jak2^VF CH is associated with atherothrombotic disease, but its mechanism is unclear. Liu et al confirmed in mouse models that Jak2^VF CH at a variable allele frequency of 1.5% is sufficient to confer an activated phenotype on both normal and Jak2^VF CH platelets, suggesting that aspirin might confer protection from atherothrombosis in patients with Jak2^VF CH.