The OTUD1-Notch2-ICD axis orchestrates allogeneic T cell-mediated graft-versus-host disease.

Disorders of the ubiquitin-proteasome system (UPS) are known to influence the incidence and mortality of various diseases. It remains largely unknown whether and how the UPS affects the onset and progression of acute graft-verus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study demonstrated that the deubiquitinase OTUD1 is an essential regulator of aGVHD. Activation of CD4+ T cells after allo-HSCT, elevated the protein levels of OTUD1, which in turn interacted with the Notch2-ICD (NICD) to cleave the ubiquitin of NICD at the K1770 site, thereby inducing NICD protein accumulations in T cells. OTUD1-driven NICD signaling promoted the differentiation and functions of Th1 and Th17 cells and amplified the cascade of aGVHD. Moreover, by screening a FDA-approved drugs library the study identified dapagliflozin as an inhibitor targeting the OTUD1/NICD axis. Dapagliflozin administration significantly prolonged the survival of aGVHD mice. This study characterized a previously unknown role of OTUD1 in T cell-mediated allogeneic responses and provided a promising therapeutic strategy to target OTUD1 for the alleviation of aGVHD.

Prognostic significance of persisting DNMT3A, ASXL1, and TET2 mutation burden in acute myeloid leukemia patients with allogeneic hematopoietic stem cell transplantation during complete remission.

We retrospectively analyzed 155 AML patients with DAT mutations at diagnosis who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at complete remission. Of the 155 AML patients with DAT mutations at diagnosis, 59 (38.1%) patients had persisting DAT mutations pretransplantation. Compared to patients with pretransplant DAT transitions, patients with persisting DAT mutation burden were shown to be older (p = 0.004), and fewer patients had TET2 mutations at diagnosis (p = 0.033). Patients with persistent DAT mutation burden had shorter overall survival (OS) (3-year OS: 59.3% vs. 83.0%, p < 0.001) and disease-free survival (DFS) (3-year DFS: 56.1% vs. 83.0%, p < 0.001) with a higher cumulative incidence of relapse (CIR) (24.6% vs. 17.4%, p = 0.002) than those with DAT transitions. Additionally, multivariate analysis confirmed that persisting DAT mutations were an independent adverse factor for relapse, OS, and DFS. Collectively, persisting DAT mutations prior to allo-HSCT at complete remission for AML correlated with negative outcomes.

Efficiency and Toxicity of Ruxolitinib as a Salvage Treatment for Steroid-Refractory Chronic Graft-Versus-Host Disease.

Graft-versus-host disease (GVHD), especially steroid-refractory GVHD, remains a life-threatening complication after hematopoietic stem cell transplantation (HSCT). The effect of the JAK1/2 kinase inhibitor ruxolitinib on treating steroid-refractory acute GVHD has been verified by the REACH1/2 study; however, its safety and efficacy in patients with steroid-refractory chronic GVHD (SR-cGVHD) remain unclear. In this retrospective study, 70 patients received ruxolitinib as a salvage therapy for SR-cGVHD. Twenty-four weeks after ruxolitinib treatment, the overall response rate (ORR) was 74.3% (52/70), including 34 patients who achieved complete remission (CR) and 18 who achieved partial remission (PR). The main adverse event was cytopenia, which occurred in 51.4% (36/70) of patients. After ruxolitinib treatment, the percentage of CD4 cells increased from 18.20% to 23.22% (P<0.001), while the percentages of NK (CD16+CD56+) cells and regulatory T cells (CD4+CD127 ± CD25+) decreased (P<0.001, P<0.001). Among the B cell subsets, the proportion of total B cells approximately tripled from 3.69% to 11.16% (P<0.001). Moreover, we observed a significant increase in IL-10 levels after ruxolitinib treatment (P=0.025) and a remarkable decrease in levels of suppression of tumorigenicity 2 (ST2) from 229.90 ng/ml to 72.65 ng/ml. The median follow-up after the initiation of ruxolitinib treatment was 401 (6-1076) days. The estimated one-year overall survival rate of the whole group was 66.0% (54.4-77.6%, 95% CI), and the one-year overall survival rate of patients with mild and moderate cGVHD was 69.6% (57.4-81.8%, 95% CI), which was better than that of patients with severe cGVHD (31.3%, 0.0-66.2%, 95% CI) (P=0.002). Patients who achieved a CR and PR achieved better survival outcomes (84.5%, 73.9-95.1%, 95% CI) than those who showed NR to ruxolitinib treatments (16.7%, 0-34.3%, 95% CI) (P<0.001). At the final follow-up, cGVHD relapse occurred in six patients after they reduced or continued their ruxolitinib doses. Collectively, our results suggest that ruxolitinib is potentially a safe and effective treatment for SR-cGVHD.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome after hematopoietic stem cell transplantation for thalassemia major: incidence, management, and outcome.

Hepatic veno-occlusive disease or sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the present prospective study, we aimed to investigate the incidence, management, and outcome of VOD/SOS in patients with thalassemia major (TM) who received allo-HSCT. VOD/SOS was diagnosed and classified based on the modified Seattle criteria. The prophylactic regimen for VOD/SOS was a combination treatment of dalteparin and lipo-PGE1. VOD/SOS was managed through an approach consisting of adequate supportive measures, short-term withdrawal of calcineurin inhibitors (CNIs), and the use of methylprednisolone and basiliximab for graft-versus-host disease prophylaxis. VOD/SOS was found in 54 of 521 patients (10.4%) at a median time of 12 days after allo-HSCT. The cumulative incidence of all-grade and moderate VOD/SOS was 10.4% and 4.2%, respectively. Among the 54 VOD/SOS patients, no patient developed severe grade and died from VOD/SOS. Besides, the cumulative incidence of transplant-related mortality on day 100 for patients with or without VOD/SOS was 0% vs. 4.0% (P = 0.187), respectively, and the 3-year overall survival rates were 94.3% vs. 93.2% (P = 0.707), respectively. Collectively, we concluded that appropriate symptomatic therapy and short-term withdrawal of CNIs safely mitigated the mortality of VOD/SOS in TM patients who underwent allo-HSCT.

Genome-scale integrated analysis to identify prospective molecular mechanisms and therapeutic targets in isocitrate dehydrogenase 2 R140Q-mutated acute myeloid leukemia.

The aim of the present study was to identify potential molecular mechanisms and therapeutic targets in regards to isocitrate dehydrogenase 2 (IDH2) R140Q-mutated acute myeloid leukemia (AML). An RNA sequencing dataset of IDH2 wild-type and R140Q-mutated adult de novo AML bone marrow samples was obtained from The Cancer Genome Atlas (TCGA) database. The edgeR package was used to screen for the differentially expressed genes (DEGs), and the potential molecular mechanisms and therapeutic targets were identified using Database for Annotation, Visualization, and Integrated Discovery (DAVID) v6.8, Biological Networks Gene Ontology tool, Connectivity Map (CMap), Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and GeneMANIA. A total of 230 DEGs were identified between the bone marrow tissues of IDH2 R140Q-mutated and wild-type AML patients, of which 31 were significantly associated with overall survival (OS). Functional assessment of DEGs showed significant enrichment in multiple biological processes, including angiogenesis and cell differentiation. STRING and GeneMANIA were used to identify the hub genes of these DEGs. CMap analysis identified 13 potential small-molecule drugs against IDH2 R140Q-mutated adult de novo AML. Genome-wide co-expression network analysis identified several IDH2 R140Q co-expressed genes, of which 56 were significantly associated with AML OS. The difference in IDH2 mRNA expression levels and OS between the IDH2 R140Q-mutated and wild-type AML were not statistically significant in our cohort. In conclusion, we identified several co-expressing genes and potential molecular mechanisms that are instrumental in IDH2 R140Q-mutated adult de novo AML, along with 13 candidate targeted therapeutic drugs.

[Clinical and Bacteriological Analysis of Bacterial Bloodstream Infections in Patients with Acute Leukemial].

OBJECTIVE: To investigate the clinical characteristics, etiology and drug susceptibility of bacterial bloodstream infections in acute leukemia(AL) patients. METHODS: Clinical data, etiology and drug susceptibility of acute leukemia patients with bacterial bloodstream infections from April 2009 to April 2018 were retrospectively analyzed. RESULTS: A total of 376 strains were isolated, 76.9% was Gram-negative bacterial and 23.1% was Gram-positive bacteria. Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae were listed as the top three of Gram-negative bacteria. The susceptibility of Escherichia coli to the tigacycline, imipenem and meropenem was 100.0%, 98.2% and 98.1%, respectively. The susceptibility of Klebsiella pneumoniae to the tigacycline, imipenem and meropenem were 100.0%, 98.3% and 94.4%, respectively. The adjustment rate for initial use of carbopenems was 3.8%, while the adjustment rate for initial use of noncarbopenems was 74.3% in patients with main Gram-negative bacterial blood stream infection. The susceptibility of Gram-positive bacteria to glycopeptide antibiotics, linezolid and tigacycline was 100.0%. CONCLUSION: Gram-negative bacteria is the majority type of bacteria in AL patients with bacteria blood stream infections. The susceptibility of Gram-negative bacteria to the carbapenems is high, and the treatment adjustment rate is obviously low. The glycopeptide, linezolid and tigacycline are effective for Gram-positive bacteria infections..