Immune-driven fibrotic skin diseases, including scleroderma/systemic sclerosis (SSc) and chronic graft-versus-host disease (GVHD), cause skin stiffening that has a major impact on patient quality of life and associated patient mortality. Therapies to improve sclerotic skin resulting from these diseases are largely ineffective. We previously showed that epiregulin (EREG), a dendritic cell type 3-derived epidermal growth factor receptor (EGFR) ligand, is elevated in the skin and lungs of patients with SSc and required for the maintenance of skin fibrosis. Here, we developed a fully human anti-EREG neutralizing antibody that has both high affinity and specificity. We found this therapeutic antibody to be functional and safe in vivo using human EREG knockin mice. To understand the antifibrotic mechanism of targeting EREG, we aligned skin single-cell transcriptomic profiles of SSc, morphea (localized scleroderma), and sclerotic GVHD (SclGVHD) with disease biomarkers. EREG expression in the skin was elevated in all 3 fibrotic diseases and is a driver of tenascin C (TNC) production by myofibroblasts. TNC is a proinflammatory extracellular glycoprotein that functions as an endogenous Toll-like receptor 4 (TLR4) ligand, which induces expression of TLR4 target genes CCL2 and interleukin-6. Examination of skin explants from patients with active SclGVHD treated with anti-EREG therapeutic antibody by spatial transcriptomics demonstrated upregulation of matrix degradation by increased MMP and decreased TIMP1 expression. Protein measurements showed reduced secretion of EREG targets TNC, CCL2, and TIMP1 in all patients and type I collagen and FN1 in three-fourths of patients. Thus, sclerotic skin treated with the anti-EREG therapeutic antibody reduced inflammatory and fibrosis biomarkers associated with EGFR and TLR4 signaling.

Marginal zone lymphoma (MZL) comprises a biologically heterogenous group of indolent B-cell lymphomas that remain substantially underrepresented in clinical research. Despite recent and significant therapeutic advances in B-cell malignancies, trial design in MZL continues to face persistent challenges, including diagnostic heterogeneity, inconsistent control arms, suboptimal end points, and economic barriers. In this narrative review, we examine these key obstacles and discuss emerging strategies to overcome them, such as the standardization of diagnostic criteria, implementation of subtype-specific treatment approaches, validation of surrogate end points, and integration of novel response assessment modalities, such as metabolic imaging (positron emission tomography), minimal residual disease assessment using flow cytometry or single-cell molecular evaluation, and circulating tumor DNA measurement, but these need to be evaluated and harmonized for full appreciation. We argue that MZL should be understood as a methodologic paradigm rather than as a clinical exception. This may facilitate the refinement of trial design and ultimately accelerate therapeutic innovation across the broad spectrum of indolent lymphomas.

Self-renewing multipotent hematopoietic stem cells (HSCs) are a rare but important cell population that can reconstitute the entire blood and immune system after transplantation. Due to their rarity, it has been difficult to comprehensively study the mechanisms regulating HSC activity. However, recent improvements in hematopoietic stem and progenitor cell (HSPC) culture methods using polyvinyl alcohol-based media now facilitate large-scale ex vivo HSC expansion. Here, we performed a genome-wide CRISPR knockout (KO) screen in primary mouse HSPCs to discover novel regulators of ex vivo expansion. The screen identified Runx2 as a strong negative regulator of HSC expansion, which we validated using ex vivo and in vivo assays. Loss of Runx2 increased the frequency of immunophenotypic HSCs in HSPC cultures by approximately threefold. After expansion, these Runx2-KO HSCs engrafted at approximately fivefold higher levels in transplantation assays. Noncultured Runx2-KO HSCs also displayed enhanced reconstitution potential, but loss of Runx2 did not alter blood parameters. Notably, however, T-cell reconstitution was diminished from Runx2-KO HSCs, and we further validated an additional role for Runx2 in T-cell commitment using ex vivo and in vivo assays. In summary, we have identified a multifaceted role for Runx2 in HSCs, as a negative regulator of HSC self-renewal and as a facilitator of T-cell commitment. These results contribute to our understanding of the transcriptional regulation of hematopoiesis and HSC therapies.

RNA splicing and processing are critical for erythropoiesis, because dysregulation of RNA splicing ultimately disrupts protein synthesis. The RNA-binding protein Rbm38 is highly expressed during terminal erythropoiesis. Although in vitro studies have implicated Rbm38 as a key regulator of erythroid differentiation, the landscape of RNA splicing regulated by Rbm38 and its role in terminal erythropoiesis in vivo have not been fully elucidated. Here, we generated whole-body and conditional knockout mouse models for Rbm38 and found that mature red blood cell (RBC) production was impaired in the bone marrow of Rbm38-deficient mice. Rbm38-/- RBCs exhibited reduced hemoglobin content and increased susceptibility to oxidative stress-induced hemolysis. These mutant mice also developed microcytic hypochromic anemia, along with dysregulated iron homeostasis. Additionally, they exhibited decreased mitochondrial heme biosynthesis and accumulation of free protoporphyrin IX (PPIX) in erythrocytes and feces, resembling human erythropoietic protoporphyria (EPP). Mechanistically, Rbm38 regulates the incorporation of ferrous iron (Fe2+) into PPIX to form heme by modulating alternative splicing, messenger RNA decay, and translation of the porphyrin metabolic enzyme gene Ferrochelatase (Fech). Importantly, enforced expression of Fech largely restored erythroid differentiation defects and ameliorated anemia in Rbm38-/- transplants. We further demonstrated that genetic variants in the human RBM38 gene locus influence PPIX levels in erythrocytes from healthy cohorts. Our findings demonstrate that Rbm38 governs terminal erythropoiesis by orchestrating RNA splicing, stability, and translation during heme biosynthesis.

The progression of multiple myeloma (MM), an incurable malignancy of plasma cells, is often associated with the suppression of ferroptosis, a type of cell death driven by iron-dependent lipid peroxidation. The mechanisms underlying this suppression remain largely unknown. Here, we identified serine/threonine kinase 17b (STK17B) kinase as a critical suppressor of ferroptosis in MM. Elevated levels of STK17B are associated with poor overall survival in patients with MM, and STK17B expression is significantly higher in relapsed vs newly diagnosed MM cases. We found that inhibiting STK17B in MM cells increased the labile iron pool, enhanced lipid peroxidation, and sensitized cells to conventional anti-MM therapies. Notably, an orally available, in-house-generated STK17B inhibitor induced ferroptosis and significantly reduced tumor growth in MM xenograft mouse models. Mechanistically, proximity labeling assay combined with the phospho-proteomic analysis identified 2 major regulators of iron uptake and transport as direct targets of STK17B: iron-responsive element binding protein 2 (IREB2), and heat shock protein family B member 1 (HSPB1). We demonstrated that STK17B phosphorylates critical regulatory sites on IREB2 (S157) and HSPB1 (S15), thereby modulating the balance between IREB2 and HSPB1 downstream effectors, proferroptotic transferrin receptor, and antiferroptotic ferritin heavy chain proteins. Furthermore, we demonstrated that STK17B indirectly maintains activating phosphorylation of STAT3, a ferroptosis suppressor and a major driver of MM pathobiology. Our findings uncovered a clinically relevant and targetable STK17B-pIREB2S157/pHSPB1S15 signaling axis that suppresses ferroptosis and contributes to drug resistance in MM.

The IELSG37 trial enrolled 545 patients with primary mediastinal B-cell lymphoma (PMBCL) and demonstrated that consolidation radiotherapy (RT) can be omitted in patients with complete metabolic response, defined by the Lugano classification as Deauville score (DS) 1 to 3. This report evaluates outcomes after different frontline rituximab- and doxorubicin-based immunochemotherapy regimens chosen according to local practice. Patients treated with R-CHOP21 (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone, administered every 21 days) showed a significantly higher percentage of DS 5 than those on other regimens (23.8% vs 8.2% average; P < .001) and a trend toward additional unplanned treatments (53.2% vs 46.9%; P = .30). The increased risk of poor response was confirmed in a multinomial logistic regression analysis adjusted for age, sex, international prognostic index score, and performance status. R-CHOP21 was also associated with smaller reductions in metabolic tumor volume and less pronounced decreases in maximum standardized uptake value. Patients with DS 5 more often received additional treatment (RT and/or salvage chemotherapy with or without autologous consolidation) after induction immunochemotherapy (96% vs 41%; P < .001) and experienced significantly poorer outcomes. Although differences in progression-free and overall survival between R-CHOP21 and more aggressive regimens were not statistically significant, R-CHOP21 may increase the risk of additional treatments and may be inadvisable as frontline therapy for PMBCL. This trial was registered at www.clinicaltrials.gov as #NCT01599559.

Human herpesvirus 6 reactivation in chimeric antigen receptor T-cell recipients is reported to be rare. Our patient cohort (n = 119) experienced a sevenfold higher incidence of viremia than a previous study and 2 cases of encephalitis. Further studies are needed to determine risk factors for infection.