Issue Archive

In this Blood Spotlight, Anderson and colleagues highlight how advances in radionuclide imaging for light-chain amyloidosis and transthyretin amyloidosis mean this noninvasive modality should be incorporated into routine practice for diagnosis and management. The authors summarize the specificity and utility of different scanning techniques in relation to different types of amyloids and illustrate just how powerful their incorporation into the early diagnostic pathway of suspected cardiac amyloidosis can be, as well as their ability to assess organ responses.

While chimeric antigen receptor (CAR) T-cell therapy is effective in several B-cell malignancies, its application against T-cell leukemia and lymphoma (T-ALL/LBL) is limited by the shared expression of CAR-targetable antigens in malignant and essential normal T cells, necessitating additional genetic manipulation. Ghobadi et al report results from a multicenter phase 1/2 study in patients with relapsed or refractory T-ALL/LBL who received 1 infusion of an allogeneic CD7-targeting T-cell product after lymphodepleting chemotherapy. After enhanced lymphodepletion, complete remissions rates are high and graft-versus-host disease uncommon, but long-term remissions require subsequent allogeneic transplantation, as CAR T-cell persistence is limited. This approach may be an effective bridge to allografting in patients with otherwise uncontrollable disease.

TET2 is mutated in approximately one-third of clonal hematopoiesis (CH) cases and encodes a dioxygenase involved in active DNA demethylation; however, how its presence causes clonal advantage is unknown. Loke and colleagues deployed a barcoded lentiviral CRISPR-Cas9 screen in vivo in mice and reveal that ferritinophagy, a selective autophagic process mediated by the cargo receptor Ncoa4, supports the expansion of Tet2-mutant stem and progenitor cells by maintaining mitochondrial iron availability and oxidative metabolism. The authors’ work pinpoints a novel metabolic dependency in Tet2-deficient CH that may be exploitable as an early intervention.

Telomere biology disorders (TBDs) are caused by germ line mutations that interfere with telomere maintenance and present to hematologists with features of bone marrow failure, variable immunodeficiency, and lung, liver, and skin disease. Through retrospective analysis of a large series of adult patients with TBD, Bazzo Catto and colleagues uncover the extent of immune abnormalities caused by accelerated immune aging and T-cell lymphopenia, demonstrating that the depth of lymphopenia correlates with bone marrow failure, increase in infection risk, and worse survival, including the association of low T-cell counts with the development of solid tumors. The authors’ work enables clinicians to readily identify those at highest risk of these manifestations.

Appropriate neutrophil recruitment to inflamed tissues depends on β₂-integrin activity, but how that is fine-tuned is unclear. Cappenberg and colleagues examine the role of the RhoA GTPase-activating protein (GAP) myosin-IXb (Myo9b) in regulating neutrophil β₂-integrin activity and recruitment. The authors combined in vitro and in vivo studies of inflammation to demonstrate that Myo9b is a crucial modulator of several key signaling pathways in neutrophils and is required for an adequate immune response triggered by chemokines and selectins.

Circulating tumor DNA (ctDNA) analyses have potential advantages in diseases such as classical Hodgkin lymphoma (cHL), where the tumors are multifocal and the pathological Reed-Sternberg cells typically make up only a minor component of the lymphoma mass. Exploiting this modality, Pirosa et al provide novel, complex insights into cHL genetics, proposing that genetic subgroups are driven by mechanisms of genetic instability and not by the functional associations of identified DNA alterations. The authors’ findings also inform identification of neoantigens and provide preliminary data suggesting that ctDNA measurement can help resolve the prognosis when posttherapy positron emission tomography imaging is equivocal.

Waldenström macroglobulinemia (WM) is an immunoglobulin M–secreting lymphoplasmacytic lymphoma thought to arise from clonal expansion of memory B cells (MBCs) driven by activating MYD88 mutation. In a single-cell multiomic study of MYD88-mutated WM, Gagler et al extend our understanding of its pathogenesis, identifying that WM includes 2 disease subtypes reflecting variable capacity for plasma cell (PC) differentiation: MBC-like and PC-like. MBC-like have more CXCR4 mutations and increased B-cell receptor signaling, whereas PC-like have more del(6q) and increased NF-kB activity, the transcriptional dysregulation leading to these distinct differentiation blocks. These data set the scene for improved clinicopathological correlation and better deployment of targeted therapies.

Nucleophosmin-1 (NPM1) mutation is the most frequent driver genetic alteration in adult acute myeloid leukemia (AML). Using AML cell lines, genetic screens, and murine models of NPM1-mutated AML, Damaskou and colleagues identified disordered ribosome function as a pathogenic consequence of NPM1 mutation and that targeted disruption of ribosome biogenesis by small molecule inhibitors of RNA polymerase I, including low-dose actinomycin-D, is an effective antileukemic strategy, especially when combined with the BCL2 inhibitor venetoclax. These insights suggest future directions for clinical trials in relapsed NPM1-mutated AML.