BCR-ABL1 tyrosine kinase sustained MECOM expression in chronic myeloid leukaemia

MECOM oncogene expression correlates with chronic myeloid leukaemia (CML) progression. Here we show that the knockdown of MECOM (E) and MECOM (ME) isoforms reduces cell division at low cell density, inhibits colony-forming cells by 34% and moderately reduces BCR-ABL1 mRNA and protein expression but not tyrosine kinase catalytic activity in K562 cells. We also show that both E and ME are expressed in CD34<sup>+</sup> selected cells of both CML chronic phase (CML-CP), and non-CML (normal) origin. Furthermore, MECOM mRNA and protein expression were repressed by imatinib mesylate treatment of CML-CP CD34<sup>+</sup> cells, K562 and KY01 cell lines whereas imatinib had no effect in non-CML BCR-ABL1 −ve CD34<sup>+</sup> cells. Together these results suggest that BCR-ABL1 tyrosine kinase catalytic activity regulates MECOM gene expression in CML-CP progenitor cells and that the BCR-ABL1 oncoprotein partially mediates its biological activity through MECOM. MECOM gene expression in CML-CP progenitor cells would provide an in vivo selective advantage, contributing to CML pathogenesis

Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms

Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2V617F-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10−10) and rs2201862 (MECOM; meta-analysis P=1.96 × 10−9). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2V617F-positive cases. rs9376092 has a stronger effect in JAK2V617F-negative cases with CALR and/or MPL mutations (Breslow–Day P=4.5 × 10−7), whereas in JAK2V617F-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ2 P=7.3 × 10−7). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype

Feeding Habits of Wisconsin\u27s Predominant Lotic Plecoptera, Ephemeroptera, and Trichoptera

Feeding habits of nymphs or larvae of 101 species of Plecoptera, Ephemeroptera, and Trichoptera collected from Wisconsin\u27s streams were determined by examining foregut contents. The percent by volume of animal, live vascular plant, filamentous algae, diatom, and detrital material recovered is reported. Plecoptera in the suborder Filipalpia were herbivoredetritivores, and most in the suborder Setipalpia were carnivores. Exceptions were Isoperla bilineata (Say), an omnivore, and Isoperla signata (Banks) and I. slossonae (Banks), both detritivore-herbivores. Except for omnivore Ephemerella cornuta Morgan, Ephemeroptera were detritivore-herbivores. Feeding habits of Trichoptera larvae were diverse. Species of Rhyacophilidae, Polycentropodidae, and Phyrganeidae were all carnivores, while Hydropsychidae, Leptoceridae, and Brachycentridae were generally omnivores. Species of Glossomatidae, Philopotamidae, Psychomyiidae, Hydroptilidae, Limnephilidae, Lepidostomatidae, Sericostomatidae, and Helicopsychidae were primarily detritivoreherbivores

Results on Transversal and Axial Motions of a System of Two Beams Coupled to a Joint through Two Legs

In recent years there has been renewed interest in inflatable-rigidizable space structures because of the efficiency they offer in packaging during boost-to-orbit. However, much research is still needed to better understand dynamic response characteristics, including inherent damping, of truss structures fabricated with these advanced material systems. We present results of an ongoing research related to a model consisting of an assembly of two beams with Kelvin-Voight damping, coupled to a simple joint through two legs. The beams are clamped at one end but at the other end they satisfy a boundary condition given in terms of an ODE coupling boundary terms of both beams, which reflects geometric compatibility conditions. The system is then written as a second order differential equation in an appropriate Hilbert space  in which well-posedness, exponential stability as well as other regularity properties of the solutions can be obtained. Two different finite dimensional approximation schemes for the solutions of the system are presented. Numerical results are presented and comparisons are made.Fil: Burns, J. A.. Interdisciplinary Center for Applied Mathematics; Estados UnidosFil: Cliff, E. M.. Interdisciplinary Center for Applied Mathematics; Estados UnidosFil: Liu, Z.. University of Minnesota at Duluth; Estados UnidosFil: Spies, Ruben Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Matemática Aplicada del Litoral. Universidad Nacional del Litoral. Instituto de Matemática Aplicada del Litoral; Argentin

Network rewiring is an important mechanism of gene essentiality change.

Gene essentiality changes are crucial for organismal evolution. However, it is unclear how essentiality of orthologs varies across species. We investigated the underlying mechanism of gene essentiality changes between yeast and mouse based on the framework of network evolution and comparative genomic analysis. We found that yeast nonessential genes become essential in mouse when their network connections rapidly increase through engagement in protein complexes. The increased interactions allowed the previously nonessential genes to become members of vital pathways. By accounting for changes in gene essentiality, we firmly reestablished the centrality-lethality rule, which proposed the relationship of essential genes and network hubs. Furthermore, we discovered that the number of connections associated with essential and non-essential genes depends on whether they were essential in ancestral species. Our study describes for the first time how network evolution occurs to change gene essentiality

Targeted sequencing of lung function loci in chronic obstructive pulmonary disease cases and controls

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide; smoking is the main risk factor for COPD, but genetic factors are also relevant contributors. Genome-wide association studies (GWAS) of the lung function measures used in the diagnosis of COPD have identified a number of loci, however association signals are often broad and collectively these loci only explain a small proportion of the heritability. In order to examine the association with COPD risk of genetic variants down to low allele frequencies, to aid fine-mapping of association signals and to explain more of the missing heritability, we undertook a targeted sequencing study in 300 COPD cases and 300 smoking controls for 26 loci previously reported to be associated with lung function. We used a pooled sequencing approach, with 12 pools of 25 individuals each, enabling high depth (30x) coverage per sample to be achieved. This pooled design maximised sample size and therefore power, but led to challenges during variant-calling since sequencing error rates and minor allele frequencies for rare variants can be very similar. For this reason we employed a rigorous quality control pipeline for variant detection which included the use of 3 independent calling algorithms. In order to avoid false positive associations we also developed tests to detect variants with potential batch effects and removed them before undertaking association testing. We tested for the effects of single variants and the combined effect of rare variants within a locus. We followed up the top signals with data available (only 67% of collapsing methods signals) in 4,249 COPD cases and 11,916 smoking controls from UK Biobank. We provide suggestive evidence for the combined effect of rare variants on COPD risk in TNXB and in sliding windows within MECOM and upstream of HHIP. These findings can lead to an improved understanding of the molecular pathways involved in the development of COPD

Persistent polyclonal binucleated B-cell lymphocytosis and MECOM gene amplification

BACKGROUND: Persistent Polyclonal Binucleated B-cell Lymphocytosis (PPBL) is characterized by a chronic polyclonal B-cell lymphocytosis with binucleated lymphocytes and a polyclonal increase in serum immunoglobulin-M. Cytogenetic is characterized by the presence of a supernumerary isochromosome +i(3)(q10), premature chromosome condensation and chromosomal instability. Outcome of PPBL patients is mostly benign, but subsequent malignancies could occur. The aim of our study is to provide an update of clinical and cytogenetic characteristics of our large cohort of PPBL patients, to describe subsequent malignancies occurring during the follow-up, and to investigate the role of the long arm of chromosome 3 in PPBL. RESULTS: We analyzed clinical, biological and cytogenetic characteristics (conventional cytogenetic analysis and fluorescent in situ hybridization) of 150 patients diagnosed with PPBL. We performed high-resolution SNP arrays in 10 PPBL patients, comparing CD19(+) versus CD19(−) lymphoid cells. We describe the cytogenetic characteristics in 150 PPBL patients consisting in the presence of supernumerary isochromosome +i(3)(q10) (59 %) and chromosomal instability (55 %). In CD19(+) B-cells, we observed recurrent copy number aberrations of 143 genes with 129 gains (90 %) on 3q and a common minimal amplified genomic region in the MECOM gene. After a median follow-up of 60 months, we observed the occurrence of 12 subsequent malignancies (12 %), 6 solid tumors and 6 Non-Hodgkin’s Lymphomas, and 6 monoclonal gammopathies of undetermined significance (MGUS), requiring a long-term clinical follow-up. CONCLUSIONS: Our clinical and cytogenetic observations lead us to hypothesize that isochromosome 3q, especially MECOM abnormality, could play a key role in PPBL