Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome

Genetic alterations disrupting the transcription factor IKZF1 (encoding IKAROS) are associated with poor outcome in B lineage acute lymphoblastic leukemia (B-ALL) and occur in >70% of the high-risk BCR-ABL1+ (Ph+) and Ph-like disease subtypes. To examine IKAROS function in this context, we have developed novel mouse models allowing reversible RNAi-based control of Ikaros expression in established B-ALL in vivo. Notably, leukemias driven by combined BCR-ABL1 expression and Ikaros suppression rapidly regress when endogenous Ikaros is restored, causing sustained disease remission or ablation. Comparison of transcriptional profiles accompanying dynamic Ikaros perturbation in murine B-ALL in vivo with two independent human B-ALL cohorts identified nine evolutionarily conserved IKAROS-repressed genes. Notably, high expression of six of these genes is associated with inferior event-free survival in both patient cohorts. Among them are EMP1, which was recently implicated in B-ALL proliferation and prednisolone resistance, and the novel target CTNND1, encoding P120-catenin. We demonstrate that elevated Ctnnd1 expression contributes to maintenance of murine B-ALL cells with compromised Ikaros function. These results suggest that IKZF1 alterations in B-ALL leads to induction of multiple genes associated with proliferation and treatment resistance, identifying potential new therapeutic targets for high-risk disease

Elastic and brittle properties of the B2-MgRE (RE=Sc, Y, Ce, Pr, Nd, Gd, Tb, Dy, Ho, Er) intermetallics

The brittle and elastic properties of the B2-MgRE (RE=Sc, Y, Ce, Pr, Nd, Gd, Tb, Dy, Ho, Er) intermetallics have been investigated using first-principles density functional calculations. The calculated equilibrium lattice constants and enthalpies of formation are in overall agreement with the available experiment and theoretical results. The related physical properties of those compounds are compared with that of ductile YCu. The Fermi energy occurs above a peak in the DOS for B2-MgRE intermetallics, whereas for ductile YCu the Fermi energy occurs near a minimum in the DOS. For B2-YCu, the partial density of states of d-states at the Fermi energy is low, while for B2-MgRE the RE d-states are partially occupied, indicating their important roles in the directional bonding for this material. The Cauchy pressure (C 12 -C 44 ) and the ratio of bulk to shear modulus B/G are used to assess the brittle/ductile behavior of B2-MgRE and YCu compounds. It can be concluded that the B2-MgRE alloys have brittle behavior. MgSc is the most brittle, and MgHo is the least brittle amongst those alloys. Copyright EDP Sciences/Società Italiana di Fisica/Springer-Verlag 200771.15.Mb Density functional theory, local density approximation, gradient and other corrections, 71.20.Lp Intermetallic compounds, 62.20.Dc Elasticity, elastic constants,

Haemopedia: An Expression Atlas of Murine Hematopoietic Cells

Hematopoiesis is a multistage process involving the differentiation of stem and progenitor cells into distinct mature cell lineages. Here we present Haemopedia, an atlas of murine gene-expression data containing 54 hematopoietic cell types, covering all the mature lineages in hematopoiesis. We include rare cell populations such as eosinophils, mast cells, basophils, and megakaryocytes, and a broad collection of progenitor and stem cells. We show that lineage branching and maturation during hematopoiesis can be reconstructed using the expression patterns of small sets of genes. We also have identified genes with enriched expression in each of the mature blood cell lineages, many of which show conserved lineage-enriched expression in human hematopoiesis. We have created an online web portal called Haemosphere to make analyses of Haemopedia and other blood cell transcriptional datasets easier. This resource provides simple tools to interrogate gene-expression-based relationships between hematopoietic cell types and genes of interest