Acute leukemia characterized by chromosomal rearrangements requires additional molecular disruptions to develop into full-blown malignancy1,2, yet the cooperative mechanisms remain elusive. Using whole-genome sequencing of a pair of monozygotic twins discordant for MLL (also called KMT2A) gene-rearranged leukemia, we identified a transforming MLL-NRIP3 fusion gene3 and biallelic mutations in SETD2 (encoding a histone H3K36 methyltransferase)4. Moreover, loss-of-function point mutations in SETD2 were recurrent (6.2%) in 241 patients with acute leukemia and were associated with multiple major chromosomal aberrations. We observed a global loss of H3K36 trimethylation (H3K36me3) in leukemic blasts with mutations in SETD2. In the presence of a genetic lesion, downregulation of SETD2 contributed to both initiation and progression during leukemia development by promoting the self-renewal potential of leukemia stem cells. Therefore, our study provides compelling evidence for SETD2 as a new tumor suppressor. Disruption of the SETD2-H3K36me3 pathway is a distinct epigenetic mechanism for leukemia development.

Acute lymphoblastic leukemia (ALL) is the most common malignancy among children. The trial Chinese Children Leukemia Group (CCLG)-ALL 2008 was a prospective clinical trial designed to improve treatment outcome of childhood ALL through the first nation-wide collaborative study in China. Totally 2231 patients were recruited from ten tertiary hospitals in eight cities. The patients were stratified according to clinical-biological characteristics and early treatment response. Standard risk (SR) and intermediate risk (IR) groups were treated with a modified BFM based protocol, and there was 25%-50% dose reduction during intensification phases in the SR group. Patients in high risk (HR) group received a more intensive maintenance treatment. Minimal residual disease (MRD) monitoring with treatment adjustment was performed in two hospitals (the MRD group). Complete remission (CR) was achieved in 2100 patients (94.1%). At five years, the estimate for overall survival (OS) and event-free survival (EFS) of the whole group was 85.3% and 79.9%, respectively. The cumulative incidence of relapse (CIR) was 15.3% at five years. The OS, EFS and CIR for the SR group were 91.5%, 87.9%, and 9.7%, respectively. The outcome of the MRD group is better than the non-MRD group (5y-EFS: 82.4% vs 78.3%, P = .038; 5y-CIR: 10.7% vs 18.0%, P < .001). Our results demonstrated that the large-scale multicenter trial for pediatric ALL was feasible in China. Dose reduction in the SR group could achieve high EFS. MRD-based risk stratification might improve the treatment outcome for childhood ALL.

© F e r r a t a S t o r t i F o u n d a t i o nmg/kg/day for at least 6 months), and methylprednisolone (2 mg/kg/day for 5 days) with subsequent halving of the dose every week until discontinuation on day 28. The dose of cyclosporine was adjusted to maintain whole blood concentrations between 150 and 250 ng/mL. Hematologic response was evaluated at 3 and 6 months after the start of therapy. The definitions of complete response, partial response, and relapse have been previously published.1 Briefly, a complete response was defined for all patients as a neutrophil count more than 1.5×10 9 /L, a platelet count more than 100×10 9 /L, and a hemoglobin level more than 11.0 g/dL. A partial response was defined as a neutrophil count more than 0.5×10 9 /L, a platelet count more than 20×10 9 /L, a hemoglobin level more than 80 g/L and no requirement for blood transfusions. Second-line therapies for non-responders to the first immunosuppressive therapy depended on the policies of the individual hospitals.The Mann-Whitney U test was used to compare continuous variables and Pearson χ 2 test was used for categorical variables. Survival rates were calculated using two methods: one indicated when data on patients were censored at the time of stem cell transplantation (transplant-free survival) and the other indicated when data on patients were not censored at the time of transplantation (overall survival).Survival rates were analyzed using the Kaplan-Meier method. Treatment groups were compared with the long-rank test. Cox proportional hazards models were used to assess which factors could predict response as well as risk factors for survival using both univariate and multivariate analyses. The estimated magnitude of the hazard ratio (HR) is shown along with the 95% confidence interval (95% CI). P values less than 0.05 are considered statistically significant.This study was approved by ethics committees of the Catholic University of Korea, Nagoya University Graduate School of Medicine, and Chinese Academy of Medical Science and Pekin Union Medical College. ResultsThe patients' characteristics are shown in Table 1. Overall, 455 patients fulfilled the eligibility criteria; 297 patients received horse ATG and 158 patients received rabbit ATG. The median follow-up periods were 82 months (range, 1 to 215 months) in the horse ATG group and 20 months (range, 1 to 182 months) in the rabbit ATG group. The median age at diagnosis was significantly older in the horse ATG group than in the rabbit ATG group. In addition, percentages of males, very severe aplastic anemia, and hepatitis-associated aplastic anemia were significantly higher in the horse ATG group than in the rabbit ATG group (Table 1).We compared hematologic responses between the horse ATG group and the rabbit ATG group (Table 2). After 3 months, in the horse ATG group, 24 (8%) patients had achieved a complete response and 112 (38%) had achieved a partial response, for an overall response rate of 46%. In the rabbit ATG group, 9 (6%) patients achieved a complete respons...

Previous studies have shown that gut microbiota can affect human immune system in many ways. Our aim was to investigate quantitative differences in fecal bacterial compositions of childhood acute lymphoblastic leukemia (ALL) patients compared to those of healthy children, so as to identify individual bacterial species that are related to the etiology of ALL. We recruited 81 subjects, including 58 patients with ALL and 23 healthy controls. Fecal samples were collected and examined by 16S rRNA quantitative arrays and bioinformatics analysis. Both Principal Coordinates Analysis (PCoA) and Non-metric Multidimensional scaling (NMDS) demonstrated that the microbial composition of ALL patients deviated from the tight cluster of healthy controls. Multiple bacterial species exhibited significant changes (e.g., Roseburia faecis, Edwardsiella tarda, and Fusobacterium naviforme) in the ALL samples. Some of the differentially abundant taxa were correlated with the level of interleukin-10. The ALL cases could be efficiently distinguished from healthy controls by the random forest model based on differential species (area under ROC curve = 0.843). Taken together, the composition of gut microbiota differed from healthy controls to pediatric ALL patients. Our study identified a series of ALL-related species in the gut microbiota, providing a new direction for future studies aiming to understand the host-gut microbiota interplay in ALL pathogenesis.