Oxidative stress is elevated in the recipients of allogeneic hematopoietic cell transplantation (allo-HCT) and likely contributes to the development of graft-versus-host disease (GVHD). GVHD is characterized by activation, expansion, cytokine production, and migration of alloreactive donor T cells, and remains a major cause of morbidity and mortality after allo-HCT. Hence, strategies to limit oxidative stress in GVHD are highly desirable. Thioredoxin-1 (Trx1) counteracts oxidative stress by scavenging ROS and regulating other enzymes that metabolize H₂O₂. The present study sought to elucidate the role of Trx1 in the pathophysiology of GVHD. Using murine and xenograft models of allogeneic bone marrow transplantation (allo-BMT) and genetic (human Trx1-Tg) as well as pharmacological (human recombinant Trx1 [RTrx1]) strategies, we found that Trx1-Tg donor T cells or administration of RTrx1 to the recipients significantly reduced GVHD severity. Mechanistically, we observed that RTrx1 reduced ROS accumulation and cytokine production of mouse and human T cells in response to alloantigen stimulation in vitro. In allo-BMT settings, we found that Trx1-Tg or RTrx1 decreased downstream signaling molecules, including NF-κB activation and T-bet expression, and reduced proliferation, IFN-γ production, and ROS accumulation in donor T cells within GVHD target organs. More importantly, administration of RTrx1 did not impair the graft-versus-leukemia effect. Taken together, the current work provides a strong rationale for, and demonstrates the feasibility of, targeting the ROS pathway, which can be readily translated to the clinic.

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT). DCs play critical roles in GVHD induction. Modulating autophagy represents a promising therapeutic strategy for the treatment of immunological diseases. Complement receptors C3aR/C5aR expressed on DCs regulate immune responses by translating extracellular signals into intracellular activity. In the current study, we found that C3aR/C5aR deficiency enhanced ceramide-dependent lethal mitophagy (CDLM) in DCs. Cotransfer of host-type C3aR ^–/– /C5aR ^–/– DCs in the recipients significantly improved GVHD outcome after allogeneic HCT, primarily through enhancing CDLM in DCs. C3aR/C5aR deficiency in the host hematopoietic compartment significantly reduced GVHD severity via impairing Th1 differentiation and donor T cell glycolytic activity while enhancing Treg generation. Prophylactic treatment with C3aR/C5aR antagonists effectively alleviated GVHD while maintaining the graft-versus-leukemia (GVL) effect. Altogether, we demonstrate that inhibiting C3aR/C5aR induces lethal mitophagy in DCs, which represents a potential therapeutic approach to control GVHD while preserving the GVL effect.

Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy originated from leukemia stem cells (LSC). Emerging evidence suggests T‐cell immunoglobulin mucin‐3(Tim3) as surface marker for LSC. However, the clinical significance and biology of Tim‐3 in AML remain to be determined, especially those LSCs. In public AML databases as well as our data, we separated AML patients into Tim‐3^high and Tim‐3^low subsets using the X‐tile software and evaluated the associations between Tim‐3 and overall survival (OS) and disease‐free survival (DFS). The Cancer Genome Atlas (TCGA) cohort revealed that high Tim‐3 expression in leukemic cells was linked with poor prognosis (DFS: p = 0.018; OS: p = 0.041). Furthermore, multiple regression analysis shows that Tim‐3 was an independent factor for the prognosis (HR = 2.26, 95% CI = 1.15–4.44, p = 0.017). Validation cohort of public gene expression omnibus (GEO) confirmed that Tim‐3 was a prognostic candidate in AML. Besides, in our internal cohort, we also confirmed that over expression of Tim‐3 protein in LSC/LPC made poor prognosis in AML. Additionally, we revealed that the LSC markers AKR1C3, CD34, and MMRN1 were upregulated in the Tim‐3^high group of TCGA. We found that the upregulated genes in the Tim‐3^high group were mainly enriched in immune response, cytokine binding and cell adhesion molecules, and JAK–STAT signaling pathway, by gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Collectively, we revealed that, for the first time, upregulation of Tim‐3 in LSCs at the level of gene and protein expression is associated with poor prognosis and the important biological feature of Tim‐3 of LSC in AML.

Purpose: We investigated whether homoharringtonine (HHT) added to venetoclax plus azacitidine (VA) could improve outcomes and counteract the negative effects of genetic patterns in patients with relapsed/refractory acute myeloid leukemia (RR-AML). Experimental Design: A multicenter retrospective cohort study of the response and genetic patterns of response to the VA plus HHT (VAH) versus the VA regimens as salvage treatment in patients with RR-AML was performed. The endpoints were the rates of composite complete remission, measurable residual disease, event-free survival, overall survival, and relapse between VAH and VA groups. Results: A total of 321 patients (VAH, n = 172; VA, n = 149) were analyzed. Compared with VA, VAH significantly improved the rates of composite complete remission (44.3% vs. 66.3%; P < 0.001), measurable residual disease negativity (34.8% vs. 59.3%; P = 0.002), prolonged overall survival (median: 15.1 months vs. not reached; P < 0.001), and event-free survival (median: 3.8 vs. 13.0 months; P < 0.001). VAH significantly mitigated the negative impact on VA efficacy of mutated FLT3-ITD/TKD, N/KRAS, and t(8;21)/AML1-ETO, as well as the relatively unfavorable effects of the TET2 and DNMT3A mutations. VAH significantly enhanced the response of patients with nonadverse European LeukemiaNet risk, with a trend toward improved response in those with adverse European LeukemiaNet risk, complex karyotype, and DNMT3A+FLT3+NPM1+. The incidence of grade 3 or higher adverse events was comparable between the two groups. Conclusions: Our findings suggest the addition of HHT to VA might enhance response and mitigate the negative impact of certain genetic patterns in RR-AML while being well tolerated.

Objective This study was to explore the changes in bacterial bloodstream infection (BSI) in patients with haematological malignancies (HMs) before and during SARS-CoV-2 pandemic. Design Retrospective cohort study between 2018 and 2021. Setting The largest haematological centre in southern China. Results A total of 599 episodes of BSI occurring in 22 717 inpatients from January 2018 to December 2021 were analysed. The frequencies of the total, Gram-negative and Gram-positive BSI before and during the pandemic were 2.90% versus 2.35% (p=0.011), 2.49% versus 1.77% (p<0.001) and 0.27% versus 0.44% (p=0.027), respectively. The main isolates from Gram-negative or Gram-positive BSI and susceptibility profiles also changed. The 30-day mortality caused by BSI was lower during the pandemic (21.1% vs 14.3%, p=0.043). Multivariate analysis revealed that disease status, pulmonary infection and shock were independent predictors of 30-day mortality. Conclusion Our data showed that the incidence of total and Gram-negative organisms BSI decreased, but Gram-positive BSI incidence increased in patients with HMs during the pandemic along with the changes of main isolates and susceptibility profiles. Although the 30-day mortality due to BSI was lower during the pandemic, the new infection prevention strategy should be considered for any future pandemics.