Transfusion-related acute lung injury (TRALI) is a leading cause of blood transfusion triggered mortality. Recently, we demonstrated the critical role of Fc-dependent complement activation in anti-CD36-mediated murine TRALI. In this study, we found that C5-/- mice were protected and administration of anti-C5 rescued wild-type mice from anti-CD36-mediated TRALI. However, C5aR1-/- mice were not protected against anti-CD36-mediated TRALI, implying a possible role of C5b-9 (membrane attack complex [MAC]). Accordingly, elevated levels of MAC were detected in bronchoalveolar lavage fluid and lung tissue of mice with anti-CD36 induced TRALI. Inhibition of MAC formation by administration of anti-C7 blocking monoclonal antibody (mAb) alleviated TRALI in mice, suggesting the critical role of the MAC in the pathology of anti-CD36-mediated TRALI. Furthermore, anti-C7 treatment also led to favorable outcome in anti-MHC I-induced murine TRALI, indicating the potential broader applicability of MAC inhibitors in the treatment of antibody-mediated TRALI. Therefore, this approach may be promising to further explore for the treatment of TRALI patients.

Macrophage activation syndrome (MAS) is believed to be the result of inappropriate proliferation and activation of the mononuclear phagocytic system. Adult-onset Still's disease (AOSD) is characterized by neutrophil activation and a cytokine storm, which can lead to its severe and potentially life-threatening complication MAS. RNA sequencing revealed that neutrophils may play a distinct and enhanced role in innate immunity in AOSD patients with MAS (AOSD-MAS). In the CpG-induced secondary hemophagocytic lymphohistiocytosis (HLH) model, depletion of neutrophils significantly reduced cytokine levels, with effects comparable to monocyte depletion. Significant enrichment was observed in the type I/II interferon and JAK-STAT pathways in neutrophils from AOSD-MAS patients. Treatment of 10 refractory AOSD-MAS patients with ruxolitinib led to the resolution of inflammatory parameters and clinical symptoms. RNA sequencing and ex vivo assays confirmed that ruxolitinib suppressed aberrant NETosis and STAT3/STAT5 signaling. In vivo, PAD4 knockout further confirmed the pathogenic role of NETosis in secondary HLH model. Moreover, selective inhibition of STAT3 or STAT5 alleviated systemic inflammation. Ten functional variants were identified in genes related to the JAK-STAT pathway, although their clinical relevance requires further validation. These findings suggest the potential of ruxolitinib in achieving disease remission in refractory AOSD-MAS patients by broadly inhibiting JAK-STAT signaling and modulation of neutrophil activation and NETosis.

No standard of care for elderly patients with aggressive adult T-cell leukemia/lymphoma (ATL) has been established. We evaluated the efficacy of CHOP every 2 weeks with mogamulizumab (Moga) (Moga-CHOP-14) for untreated elderly patients with ATL. In this multicenter phase 2 trial, patients aged ≥66 years and those aged 56-65 years ineligible for transplantation received 6 cycles of Moga-CHOP-14, followed by 2 cycles of Moga monotherapy. The primary endpoint was 1-year progression-free survival (PFS). Secondary endpoints were the complete response (CR) rate, overall response rate (ORR), overall survival (OS), 1-year event-free survival (EFS), and safety. We also investigated the impact of CCR4 mutation and Moga-associated cutaneous adverse events (cAEs) on PFS and OS. The study protocol was amended to allow the dosing interval to be extended to 21 days at the physician's discretion. Among 48 evaluable patients, the 1-year PFS was 36.2% (90% confidence interval [CI], 24.9-47.6), with a median follow-up of 1.6 years. One-year OS and EFS were 66.0% (95% CI, 50.6-77.6) and 29.9% (95% CI, 17.6-43.2), respectively. CR and ORR were 64.6% (95%CI, 49.5-77.8) and 91.7% (95% CI, 80.0-97.7). No unexpected toxicities were observed. Of the 47 patients who received ≥2 cycles of CHOP, 20 (42.6%) received CHOP-14, among whom 12 (25.5%) completed 6 cycles. CCR4 mutation and Moga-associated cAE were associated with better OS. This study showed that Moga-CHOP significantly improved PFS, though the optimal interval for CHOP remains undetermined. Moga-CHOP is now considered a preferable first-line treatment for these patients. Clinical Trial Identifier: jRCTs041180130.

Myeloproliferative neoplasms (MPNs) are hematopoietic stem cell-driven malignancies marked by excessive myelopoiesis and high risk of myelofibrosis, which remains therapeutically challenging. Senescent neutrophils home daily to the bone marrow (BM) to be cleared by macrophages. This avoids their accumulation, which can increase the risk of chronic inflammation or oncogenesis. Neutrophils carrying the most common oncogenic MPN driver (JAK2V617F) are protected from apoptosis, which may prolong their lifespan and enhance their pro-inflammatory activity. On the other hand, abnormal interactions of neutrophils with megakaryocytes ("emperipolesis") have been associated with BM fibrosis in disparate hematological disorders, including MPN and grey platelet syndrome; however, the underlying pathophysiology remains unclear. We investigated neutrophil homeostasis and cellular interactions in MPN. We found that senescent neutrophils evade homeostatic clearance and accumulate in JAK2V617F MPN, but not in MPN caused by the second most prevalent mutations affecting Calreticulin (CALR) gene. This is explained by GM-CSF-JAK2-STAT5-dependent upregulation of the "don't-eat-me" signal CD24 in neutrophils. Mechanistically, JAK2V617F CD24hi neutrophils evade efferocytosis, invade megakaryocytes and increase active TGF-b. Collectively, JAK2V617F neutrophil-megakaryocyte interactions promote platelet production in a humanized bioreactor and myelofibrosis in mouse models. Notably, chronic antibody blockade or genetic loss of CD24 restores clearance of senescent neutrophils, reduces emperipolesis and active TGF-b. Consequently, CD24 blockade improves thrombocytosis and prevents myelofibrosis in MPN mice. Taken together, these findings reveals defective neutrophil clearance as a cause of pathogenic microenvironmental interactions of inflammatory neutrophils with megakaryocytes, associated with myelofibrosis in MPN. Our study postulate CD24 as a candidate innate immune checkpoint in MPN.

As evidenced by the excellent survival outcomes, chronic myeloid leukemia (CML) treatment in the era of tyrosine kinase inhibitors (TKIs) is often successful. However, when response milestones are not met or lost, treatment decision-making may be challenging. The availability for first-, second- or subsequent-line use of six different TKIs, each with definite and often non-overlapping features in terms of mechanism of action, potency, activity against resistance mutations and tolerability profile provides a reassuring opportunity to rescue an optimal response, but it must be exploited carefully to avoid hasty or inappropriate choices. When and how to sequence TKIs, and if and when to consider transplant are very important issues. 'One for all' rules cannot be formulated, since for each individual patient the decision process requires investigation and integration of a series of clinical and biological factors. After discussing how resistance is defined, we here aim to provide practical guidance to therapeutic reassessment, discussing which laboratory investigations should be performed, how they should be interpreted, which additional clinical considerations are mandatory, and how these factors should be weighed and reasonably concur to the final decision.

Sepsis is characterized by a systemic inflammation and microvascular thrombosis induced by infection. NLRP6 possesses both pro- and anti-inflammatory effects with cell-type- or tissue-specific functions. However, the role of cell-type-specific NLRP6 in sepsis remains poorly understood. In the present study, we detected NLRP6 expression in platelets. By using platelet-specific NLRP6 knockout mice and the cecal ligation and puncture model of sepsis, we demonstrated that deletion of platelet NLRP6 increased the mortality, enhanced microvascular thrombosis in the lung and liver, and promoted platelet activation, platelet-neutrophil interactions as well as the neutrophil extracellular traps (NETs) formation following sepsis. Platelet function analysis in vitro showed that deletion of NLRP6 enhanced platelet aggregation, activation, and granules release. In addition, NLRP6 deletion promoted platelet NF-κB signaling via sustaining TAB1 expression independent of the inflammasome. Moreover, inhibition of NF-κB signaling abolished the aggravated effects of the absence of platelet NLRP6 on the intravascular microthrombosis and NETs formation in sepsis and increased the overall survival. Mechanistically, NLRP6 facilitated the interaction between TRIM21 and TAB1 in activated platelets, resulting in K48-linked polyubiquitination of TAB1 and subsequent degradation. Finally, sepsis plasma triggered TAB1 degradation mediated by NLRP6/TRIM21 in normal healthy platelets through TLR4/MyD88. Our study identifies a novel protective role of platelet NLRP6 in the microvascular thrombosis during sepsis, implying it as a novel target for the treatment of sepsis.

While the majority of patients with follicular lymphoma (FL) follow an indolent disease course, some patients experience a critical inflection point when FL transforms into an aggressive lymphoma. Historically, FL transformation (tFL) is marked by poor outcomes, particularly for patients with prior FL-directed treatment. Compared to FL, tFL is marked by numerous additional genetic changes, upregulates novel signaling pathways and arises from an ancestral FL clone with shared FL-initiating mutations. Prediction of tFL risk remains a high-priority area of disease research, with recent work highlighting memory-like B cell phenotypes associated with transformation risk and implicating critical tumor-immune interactions at transformation emergence. Mechanistic studies provide insight into the role of genetic drivers in determining malignant B cell phenotypes or reducing microenvironmental dependencies. In parallel, a shifting therapeutic landscape marked by novel immune-based therapeutics is improving outcomes for patients, yet further clinical outcome data in tFL are greatly needed. This review summarizes recent scientific and clinical studies in tFL and provides an updated understanding of the biological basis, diagnosis and clinical management of tFL. We conclude with a proposed plan of future research aimed at the goal of increasing tFL biologic knowledge and improving outcomes for patients with tFL.

VEXAS (Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic) syndrome is a severe monogenic disorder caused by somatic UBA1 mutations, characterized by inflammation, cytopenias and frequent association with myelodysplastic neoplasms (MDS). Steroid dependence is common, and targeted therapies have demonstrated limited efficacy. Azacitidine (AZA), a hypomethylating agent used in MDS, has shown potential in VEXAS but data remain limited. This multicenter retrospective study assessed AZA efficacy and safety in 88 genetically confirmed VEXAS patients from the FRENVEX (French VEXAS) group, 80% meeting WHO 2022 MDS criteria. Inflammatory response rates were 41% at 6 months and 54% at 12 months, regardless of MDS status. A total of 50 (61%) patients achieved inflammatory response, with 70% occurring at 6 months, suggesting a delayed median response. Among responders, relapse-free survival on AZA was 90% at 1 year and 85% at 5 years. Of the 12 responders who discontinued AZA, 9 relapsed after a median of 3.1 years (range: 0.4-5.6), with effective re-exposure in 4 of 5 patients. Hematological responses included red blood cell transfusion independence in 65% and platelet improvement in 77% of patients. Molecular response, defined as a ≥25% reduction in UBA1 variant allele frequency (VAF), was observed in 65% of patients, all of whom achieved inflammatory and hematological responses; and VAF dropped below 2% in 43% of cases. Infections (34%) and cytopenias (36%) were common, particularly during the first three cycles. This study establishes AZA as an effective therapy for VEXAS, improving inflammation, cytopenias, and UBA1 clonal burden, warranting larger prospective trials.