Issue Archive

Beyond their role in hemostasis and thrombosis, platelets are now known to be important in inflammation, sepsis, cancer, and vascular integrity. Edited by Elisabeth M. Battinelli, this Review Series explores the basis of this versatility—not all platelets are alike. Kaiser et al define the different characteristics that can differentiate platelet subpopulations, key disease associations, and how disease can modify platelet phenotype. Malloy et al further define platelet subpopulations functionally, describing their function in vascular repair, immune mediation, infection, and angiogenesis. They highlight how the location of platelets’ birth from megakaryocytes dictates some of these characteristics. Thiele et al discuss laboratory and clinical methods of identifying platelet subpopulations, addressing technical issues in subpopulation identification and looking forward to how we can clinically integrate platelet subtyping.

Intestinal iron absorption is tightly controlled to maintain iron homeostasis, with the hormone hepcidin a key negative regulator of ferroportin-mediated iron export from enterocytes into the blood. While most hepcidin is produced by the liver, it can be produced in the intestine. In a Plenary Paper, Falabrègue and colleagues identify a new function for hepcidin, showing that it also acts within the intestinal lumen to target the iron importer divalent metal ion transporter 1 (DMT1) and block iron absorption. Their work indicates that iron absorption from the apical surface of enterocytes can be modulated through manipulation of the hepcidin-DMT1 interaction, opening new avenues for research and therapeutic manipulation.

Beyond their role in hemostasis and thrombosis, platelets are now known to be important in inflammation, sepsis, cancer, and vascular integrity. Edited by Elisabeth M. Battinelli, this Review Series explores the basis of this versatility—not all platelets are alike. Kaiser et al define the different characteristics that can differentiate platelet subpopulations, key disease associations, and how disease can modify platelet phenotype. Malloy et al further define platelet subpopulations functionally, describing their function in vascular repair, immune mediation, infection, and angiogenesis. They highlight how the location of platelets’ birth from megakaryocytes dictates some of these characteristics. Thiele et al discuss laboratory and clinical methods of identifying platelet subpopulations, addressing technical issues in subpopulation identification and looking forward to how we can clinically integrate platelet subtyping.

Beyond their role in hemostasis and thrombosis, platelets are now known to be important in inflammation, sepsis, cancer, and vascular integrity. Edited by Elisabeth M. Battinelli, this Review Series explores the basis of this versatility—not all platelets are alike. Kaiser et al define the different characteristics that can differentiate platelet subpopulations, key disease associations, and how disease can modify platelet phenotype. Malloy et al further define platelet subpopulations functionally, describing their function in vascular repair, immune mediation, infection, and angiogenesis. They highlight how the location of platelets’ birth from megakaryocytes dictates some of these characteristics. Thiele et al discuss laboratory and clinical methods of identifying platelet subpopulations, addressing technical issues in subpopulation identification and looking forward to how we can clinically integrate platelet subtyping.

Beyond their role in hemostasis and thrombosis, platelets are now known to be important in inflammation, sepsis, cancer, and vascular integrity. Edited by Elisabeth M. Battinelli, this Review Series explores the basis of this versatility—not all platelets are alike. Kaiser et al define the different characteristics that can differentiate platelet subpopulations, key disease associations, and how disease can modify platelet phenotype. Malloy et al further define platelet subpopulations functionally, describing their function in vascular repair, immune mediation, infection, and angiogenesis. They highlight how the location of platelets’ birth from megakaryocytes dictates some of these characteristics. Thiele et al discuss laboratory and clinical methods of identifying platelet subpopulations, addressing technical issues in subpopulation identification and looking forward to how we can clinically integrate platelet subtyping.

CD38 and G protein–coupled receptor class C group 5 member D (GPRC5D) are both bona fide cell surface targets in multiple myeloma (MM). The anti-CD38 monoclonal antibody daratumumab not only directly reduces MM cells but potentiates bispecific antibody activity in preclinical models. In a phase 1b/2 trial of 65 heavily pretreated patients with MM, Chari et al combined daratumumab and talquetamab, a GPRC5D-targeting bispecific antibody, reporting depletion of CD38-expressing regulatory T cells following daratumumab and impressive efficacy, with an 80% overall (57% complete) response rate and median progression-free survival of 23.3 months. Toxicity was significant, in line with that expected from each agent, but discontinuations due to adverse events were uncommon. This regimen is now being evaluated in a phase 3 trial.

CUX1 is a homeodomain transcription factor whose mutation or loss in myeloid neoplasms, such as those with monosomy 7 or del(7q), is associated with poor prognosis. Martinez et al reveal that CUX1 regulates hematopoietic stem cell (HSC) fate in a dose-dependent fashion, with expression increasing as differentiation progresses. CUX1 normally suppresses endogenous retroelements (EREs), and reduced CUX1 allows ERE-driven interferon signaling, which in turn sustains stemness through intrinsic immune activation. These surprising results add to the functions ascribed to CUX1 and call for further research into how CUX1 regulates normal and malignant myelopoiesis.

Both multiple myeloma (MM) cells and T cells have a preferential dependency upon glutamine. Higher-level expression of the gene encoding the glutamine transporter ASCT2 by MM cells in patients is associated with a worse prognosis, and, in vitro, glutamine is limiting for action of chimeric antigen receptor (CAR) T cells. Using an immunocompetent murine model of MM, Navarro and colleagues explored whether modulating glutamine uptake by T cells can improve outcomes and demonstrated that enhancing glutamine uptake by B-cell maturation antigen (BCMA) CAR T cells through overexpression of Asct2 increases in vivo anti-MM efficacy.

While t(8:21) acute myeloid leukemia (AML) has a favorable prognosis, recurrences are common and new therapies are needed. Derevyanko and colleagues used an innovative lipid nanoparticle (LNP) delivery system and chemically modified small interfering RNAs (siRNAs) to target the RUNX1::RUNX1T1 fusion breakpoint in samples from patients with t(8:21) AML. They found that transient silencing of RUNX1::RUNX1T1 fusion gene expression is sufficient to decrease stem cell self-renewal and cause partial myeloid differentiation. These data reveal insights into the requirement for expression of the fusion and may suggest a future therapeutic pathway.

A unique effector mechanism engaged by neutrophils is expulsion of their DNA contents to form neutrophil extracellular traps (NETs). Thomas et al explored how the complement system can instigate NET release after priming by lipopolysaccharide. They report that such NETs are less procoagulant than NETs induced in other ways, suggesting a capacity for neutrophils to tune their own inflammatory reactions via molecular feedback loops.