BackgroundWheat grains are an important source of food, stock feed and raw materials for industry, but current production levels cannot meet world needs. Elucidation of the molecular mechanisms underlying wheat grain development will contribute valuable information to improving wheat cultivation. One of the most important mechanisms implicated in plant developmental processes is the ubiquitin-proteasome system (UPS). Among the different roles of the UPS, it is clear that it is essential to hormone signaling. In particular, E3 ubiquitin ligases of the UPS have been shown to play critical roles in hormone perception and signal transduction.ResultsA NimbleGen microarray containing 39,179 UniGenes was used to study the kinetics of gene expression during wheat grain development from the early stages of cell division to the mid-grain filling stage. By comparing 11 consecutive time-points, 9284 differentially expressed genes were identified and annotated during this study. A comparison of the temporal profiles of these genes revealed dynamic transcript accumulation profiles with major reprogramming events that occurred during the time intervals of 80-120 and 220-240°Cdays. The list of the genes expressed differentially during these transitions were identified and annotated. Emphasis was placed on E3 ligase and hormone-related genes. In total, 173 E3 ligase coding genes and 126 hormone-related genes were differentially expressed during the cell division and grain filling stages, with each family displaying a different expression profile.ConclusionsThe differential expression of genes involved in the UPS and plant hormone pathways suggests that phytohormones and UPS crosstalk might play a critical role in the wheat grain developmental process. Some E3 ligase and hormone-related genes seem to be up- or down-regulated during the early and late stages of the grain development.
Background: Persistence of miminal residual disease (MRD) is a strong indicator for drug resistance in acute lymphoblastic leukemia (ALL). The contribution of the bone marrow microenvironment to resistance remains incompletely understood. In-vivo imaging in a murine model of T-cell ALL (T-ALL) infirm the existence of distinct predilection sites for leukemia cells in the bone marrow. A recent report based on experiments with patient-derived-xenografts (PDX) has suggested a role for a dormant subpopulation in B-cell precursor ALL (BCP-ALL), possibly in vicinity to the bone endothelium, to confer chemoresistence. Aims: We here set out to compare the topology of the bone marrow microenvironment in primary patient-derived BCP-and T-ALL under therapeutic pressure in PDX models. Methods: We established a PDX model of ALL induction chemotherapy with Dexamethasone, Vincristine and Doxorubicin in NOD/scid ILR-2gamma null mice and analyzed the distribution of residual ALL cells in relation to bone and vascular structures using 3D confocal immunofluorescence microscopy of different bones at specific timepoints before and after treatment. We used cell-type specific immunofluorescence staining combined with 3D confocal z-stack tiling and applied distance analysis algorithms to define the cellular components of the leukemia niche. Results: Analyzing long bones from 5 BCP-ALL and 3 T-ALL PDX both at early engraftment (4 or 11 days after transplantation) and at MRD (after induction chemotherapy), we show that BCP-ALL cells are located in close contact to the extravascular side of endothelial cells of bone marrow sinusoids. BCP-ALL cells were enriched within a distance below 5 mm from endothelial cells and reproducibly more distant from arterioles and transition zones. In contrast, T-ALL PDX at early engraftment and after induction chemotherapy were spread over the bone marrow with a marked tendency to cluster close to the endosteum after induction chemotherapy (~30 % of all T-ALL cells). We next attempted to identify subsets with slow cell cycle rates using Carboxyfluoresceinsuccinimidylester (CFSE) labelled ALL PDX. In our model of induction chemotherapy, proliferation of BCP-as well as T-ALL cells was transiently decelerated. However, we could not detect any persistence of a reproducible population with reduced proliferative activity, challenging the notion that a dormant ALL subpopulation can be detected by this approach. Moreover, residual CFSE retaining cells after chemotherapy localized next to bone marrow sinusoids for BCP-ALL and more widespread within the bone marrow for T-ALL. Finally, we confirm an increase of CFSE retention in distal adipocytic rich yellow bone marrow (e.g. tail vertebra) compared to the red bone marrow of long bones, suggesting differences that may impact on the activity of therapeutic agents targeting rapidly cycling leukemia cells. Summary/Conclusion: Our data reconcile previous reports by revealing robust differences between BCP-and T-ALL with respect to the topology of the leukemia niche in MRD. ...
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