Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R) and 20 older children (MLL-R cases) with leukemia. Our data demonstrated infant MLL-R ALL to have one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite the paucity of mutations, activating mutations in kinase/PI3K/RAS signaling pathways were detected in 47%. Surprisingly, however, these mutations were often sub-clonal and frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (a mean of 6.5/case versus 1.3/case, P=7.15×10−5) and contained frequent mutations (45%) in epigenetic regulators, a category of genes that with the exception of MLL was rarely mutated in infant MLL-R ALL.

The increased prevalence of high temperatures (HTs) around the world is a major global concern, as they dramatically affect agronomic productivity. Upon HT exposure, plants sense the temperature change and initiate cellular and metabolic responses that enable them to adapt to their new environmental conditions. Decoding the mechanisms by which plants cope with HT will facilitate the development of molecular markers to enable the production of plants with improved thermotolerance. In recent decades, genetic, physiological, molecular, and biochemical studies have revealed a number of vital cellular components and processes involved in thermoresponsive growth and the acquisition of thermotolerance in plants. This review summarizes the major mechanisms involved in plant HT responses, with a special focus on recent discoveries related to plant thermosensing, heat stress signaling, and HT-regulated gene expression networks that promote plant adaptation to elevated environmental temperatures.

Background: Variability in metabolic parameters, such as fasting blood glucose and cholesterol concentrations, blood pressure, and body weight can affect health outcomes. We investigated whether variability in these metabolic parameters has additive effects on the risk of mortality and cardiovascular outcomes in the general population. Methods: Using nationally representative data from the Korean National Health Insurance System, 6 748 773 people who were free of diabetes mellitus, hypertension, and dyslipidemia and who underwent ≥3 health examinations from 2005 to 2012 were followed to the end of 2015. Variability in fasting blood glucose and total cholesterol concentrations, systolic blood pressure, and body mass index was measured using the coefficient of variation, SD, variability independent of the mean, and average real variability. High variability was defined as the highest quartile of variability. Participants were classified numerically according to the number of high-variability parameters (eg, a score of 4 indicated high variability in all 4 metabolic parameters). Cox proportional hazards models adjusting for age, sex, smoking, alcohol, regular exercise, income, and baseline levels of fasting blood glucose, systolic blood pressure, total cholesterol, and body mass index were used. Results: There were 54 785 deaths (0.8%), 22 498 cases of stroke (0.3%), and 21 452 myocardial infarctions (0.3%) during a median follow-up of 5.5 years. High variability in each metabolic parameter was associated with a higher risk for all-cause mortality, myocardial infarction, and stroke. Furthermore, the risk of outcomes increased significantly with the number of high-variability metabolic parameters. In the multivariable-adjusted model comparing a score of 0 versus 4, the hazard ratios (95% CIs) were 2.27 (2.13–2.42) for all-cause mortality, 1.43 (1.25–1.64) for myocardial infarction, and 1.41 (1.25–1.60) for stroke. Similar results were obtained when modeling the variability using the SD, variability independent of the mean, and average real variability, and in various sensitivity analyses. Conclusions: High variability of fasting blood glucose and total cholesterol levels, systolic blood pressure, and body mass index was an independent predictor of mortality and cardiovascular events. There was a graded association between the number of high-variability parameters and cardiovascular outcomes.

BACKGROUND Allogeneic hematopoietic stem-cell transplantation for X-linked severe combined immunodeficiency (SCID-X1) often fails to reconstitute immunity associated with T cells, B cells, and natural killer (NK) cells when matched sibling donors are unavailable unless high-dose chemotherapy is given. In previous studies, autologous gene therapy with γ-retroviral vectors failed to reconstitute B-cell and NK-cell immunity and was complicated by vector-related leukemia. METHODS We performed a dual-center, phase 1–2 safety and efficacy study of a lentiviral vector to transfer IL2RG complementary DNA to bone marrow stem cells after low-exposure, targeted busulfan conditioning in eight infants with newly diagnosed SCID-X1. RESULTS Eight infants with SCID-X1 were followed for a median of 16.4 months. Bone marrow harvest, busulfan conditioning, and cell infusion had no unexpected side effects. In seven infants, the numbers of CD3+, CD4+, and naive CD4+ T cells and NK cells normalized by 3 to 4 months after infusion and were accompanied by vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors. The eighth infant had an insufficient T-cell count initially, but T cells developed in this infant after a boost of gene-corrected cells without busulfan conditioning. Previous infections cleared in all infants, and all continued to grow normally. IgM levels normalized in seven of the eight infants, of whom four discontinued intravenous immune globulin supplementation; three of these four in-fants had a response to vaccines. Vector insertion-site analysis was performed in seven infants and showed polyclonal patterns without clonal dominance in all seven. CONCLUSIONS Lentiviral vector gene therapy combined with low-exposure, targeted busulfan conditioning in infants with newly diagnosed SCID-X1 had low-grade acute toxic effects and resulted in multilineage engraftment of transduced cells, reconstitution of functional T cells and B cells, and normalization of NK-cell counts during a median follow-up of 16 months. (Funded by the American Lebanese Syrian Associated Charities and others; LVXSCID-ND ClinicalTrials.gov number, .)

After hematopoietic stem cell transplantation (HSCT), successful engraftment and immune recovery is necessary to protect the patient from relapse and infection. Many studies highlight the importance of conventional αβ T cell recovery after HSCT but the impact of γδ T cell recovery has not been well described. Here, we investigate the recovery of γδ T cells in 102 pediatric patients with acute leukemia in first clinical remission that underwent an allogeneic HSCT at St. Jude Children’s Research Hospital from 1996-2011. The mean age of the patients was 10.5 ± 5.9 years (range, 0.6-25.2) and the mean follow up of the survivors was 2.7±1.8 years (range 0.12-6.0). Diagnoses included 59% patients with ALL and 41% patients with AML. Multivariate analysis demonstrated significant impact of the maximum number of CD3+, CD4+ and CD8+ T cells and donor source on the γδ T cell recovery (P<0.0001, P<0.0001, P<0.0001 and P <0.004; respectively). Univariate and multivariate model found the number of γδ T cells after HSCT to be associated with infections (P = 0.026 and P = 0.02, respectively). We found the probability of infections for patients with an elevated number of γδ T cells was significantly lower compared to patients with low or normal γδ T cells after HSCT (18% vs. 54%; P=0.025). Bacterial infections were not observed in patients with elevated γδ T cells. Lastly, event free survival was significantly higher in patients with enhanced γδ T cell reconstitution compared to patients with low/normal γδ T cell reconstitution after HSCT (91% vs. 55%; P=0.04). Thus, γδ T cell may play an important role in immune reconstitution after HSCT.