Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukemia

Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2DBCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered.This work was supported in part by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital; by a Stand Up to Cancer Innovative Research Grant and St. Baldrick’s Foundation Scholar Award (to C.G.M.); by a St. Baldrick’s Consortium Award (S.P.H.), by a Leukemia and Lymphoma Society Specialized Center of Research grant (S.P.H. and C.G.M.), by a Lady Tata Memorial Trust Award (I.I.), by a Leukemia and Lymphoma Society Special Fellow Award and Alex’s Lemonade Stand Foundation Young Investigator Awards (K.R.), by an Alex’s Lemonade Stand Foundation Award (M.L.) and by National Cancer Institute Grants CA21765 (St Jude Cancer Center Support Grant), U01 CA157937 (C.L.W. and S.P.H.), U24 CA114737 (to Dr Gastier-Foster), NCI Contract HHSN261200800001E (to Dr Gastier-Foster), U10 CA180820 (ECOG-ACRIN Operations) and CA180827 (E.P.); U10 CA180861 (C.D.B. and G.M.); U24 CA196171 (The Alliance NCTN Biorepository and Biospecimen Resource); CA145707 (C.L.W. and C.G.M.); and grants to the COG: U10 CA98543 (Chair’s grant and supplement to support the COG ALL TARGET project), U10 CA98413 (Statistical Center) and U24 CA114766 (Specimen Banking). This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract Number HHSN261200800001E

Interactions between Glucocorticoid Treatment and Cis-Regulatory Polymorphisms Contribute to Cellular Response Phenotypes

Glucocorticoids (GCs) mediate physiological responses to environmental stress and are commonly used as pharmaceuticals. GCs act primarily through the GC receptor (GR, a transcription factor). Despite their clear biomedical importance, little is known about the genetic architecture of variation in GC response. Here we provide an initial assessment of variability in the cellular response to GC treatment by profiling gene expression and protein secretion in 114 EBV-transformed B lymphocytes of African and European ancestry. We found that genetic variation affects the response of nearby genes and exhibits distinctive patterns of genotype-treatment interactions, with genotypic effects evident in either only GC-treated or only control-treated conditions. Using a novel statistical framework, we identified interactions that influence the expression of 26 genes known to play central roles in GC-related pathways (e.g. NQO1, AIRE, and SGK1) and that influence the secretion of IL6

The Development and Evaluation of a K-12 Land Use Environmental Education Conceptual Guide and On-Line Course

At the current rate of development, population growth, and consumption we are depleting the world's important and finite natural resources including the land. Urban, suburban, and rural sprawl threatens our air and water quality, habitat and biodiversity, and the unique characteristics of our communities. Land use environmental education works towards and promotes sustainability by helping students and educators understand the relationship between the social, environmental, and economic structures within our communities and the world. The Center for Land Use Education had produced a conceptual framework that identified 68 concepts that should be included in the development of a land use curriculum. This project continued the creation of a guiding tool for land use environmental education through the development and evaluation of the suggested scope and sequence, a conceptual guide for K-12 land use environmental education in Wisconsin, the Creative Land Use Series for Teachers and Educator Resources (CLUSTER), and an on-line professional development course for educators, Natural Resources 780-Land Use Education and Resources for Teachers. The suggested scope and sequence links the land use concepts with the Wisconsin Model Academic standards for social studies and environmental education and was validated and evaluated by a validity panel of selected Wisconsin educators. CLUSTER was developed to provide educators a practical resource for the creation and infusion of land use issues and concepts into the K-12 curriculum and evaluated by a team of educators and professionals from across the nation. The on-line course, Land Use Education and Resources for Teachers, was developed to introduce and familiarize educators with the concepts, issues, and available resources relating to the topic of land use and to teach educators how to use, adapt, create, and infuse land use activities and lessons into their existing curriculum. The course was piloted and evaluated by a team of educators and professional from across the nation. This completed project is the first comprehensive resource regarding land use education and provides educators with the knowledge, skills, and tools to infuse land use concepts into the K-12 curriculum. This Wisconsin based project is expected to grow into a national project through the creation of an K-12 land use activity guide that will link land use concepts to the national standards across all subject areas. The goal is that land use environmental education will aid in the development of informed citizens that can understand the essence of the lands capacity and potential in the past, present and future, and have the skills and tools to make informed choices.Wisconsin Environmental Education Board, Environmental Protection Agency, and the Global Environmental Education Management Cente