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      Potential Role of Notch Signalling in CD34 + Chronic Myeloid Leukaemia Cells: Cross-Talk between Notch and BCR-ABL

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          Abstract

          Notch signalling is critical for haemopoietic stem cell (HSC) self-renewal and survival. The role of Notch signalling has been reported recently in chronic myeloid leukaemia (CML) – a stem cell disease characterized by BCR-ABL tyrosine kinase activation. Therefore, we studied the relationship between BCR-ABL and Notch signalling and assessed the expression patterns of Notch and its downstream target Hes1 in CD34 + stem and progenitor cells from chronic-phase CML patients and bone marrow (BM) from normal subjects (NBM). We found significant upregulation ( p<0. 05) of Notch1, Notch2 and Hes1 on the most primitive CD34 +Thy + subset of CML CD34 + cells suggesting that active Notch signalling in CML primitive progenitors. In addition, Notch1 was also expressed in distinct lymphoid and myeloid progenitors within the CD34 + population of primary CML cells. To further delineate the possible role and interactions of Notch with BCR-ABL in CD34 + primary cells from chronic-phase CML, we used P-crkl detection as a surrogate assay of BCR-ABL tyrosine kinase activity. Our data revealed that Imatinib (IM) induced BCR-ABL inhibition results in significant ( p<0. 05) upregulation of Notch activity, assessed by Hes1 expression. Similarly, inhibition of Notch leads to hyperactivation of BCR-ABL. This antagonistic relationship between Notch and BCR-ABL signalling was confirmed in K562 and ALL-SIL cell lines. In K562, we further validated this antagonistic relationship by inhibiting histone deacetylase (HDAC) - an effector pathway of Hes1, using valproic acid (VPA) - a HDAC inhibitor. Finally, we also confirmed the potential antagonism between Notch and BCR/ABL in In Vivo, using publically available GSE-database, by analysing gene expression profile of paired samples from chronic-phase CML patients pre- and post-Imatinib therapy. Thus, we have demonstrated an antagonistic relationship between Notch and BCR-ABL in CML. A combined inhibition of Notch and BCR-ABL may therefore provide superior clinical response over tyrosine-kinase inhibitor monotherapy by targeting both quiescent leukaemic stem cells and differentiated leukaemic cells and hence must be explored.

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          PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes.

          DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1alpha and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.
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            Adjusting batch effects in microarray expression data using empirical Bayes methods.

            Non-biological experimental variation or "batch effects" are commonly observed across multiple batches of microarray experiments, often rendering the task of combining data from these batches difficult. The ability to combine microarray data sets is advantageous to researchers to increase statistical power to detect biological phenomena from studies where logistical considerations restrict sample size or in studies that require the sequential hybridization of arrays. In general, it is inappropriate to combine data sets without adjusting for batch effects. Methods have been proposed to filter batch effects from data, but these are often complicated and require large batch sizes ( > 25) to implement. Because the majority of microarray studies are conducted using much smaller sample sizes, existing methods are not sufficient. We propose parametric and non-parametric empirical Bayes frameworks for adjusting data for batch effects that is robust to outliers in small sample sizes and performs comparable to existing methods for large samples. We illustrate our methods using two example data sets and show that our methods are justifiable, easy to apply, and useful in practice. Software for our method is freely available at: http://biosun1.harvard.edu/complab/batch/.
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              The Notch signalling system: recent insights into the complexity of a conserved pathway.

              Notch signalling links the fate of one cell to that of an immediate neighbour and consequently controls differentiation, proliferation and apoptotic events in multiple metazoan tissues. Perturbations in this pathway activity have been linked to several human genetic disorders and cancers. Recent genome-scale studies in Drosophila melanogaster have revealed an extraordinarily complex network of genes that can affect Notch activity. This highly interconnected network contrasts our traditional view of the Notch pathway as a simple linear sequence of events. Although we now have an unprecedented insight into the way in which such a fundamental signalling mechanism is controlled by the genome, we are faced with serious challenges in analysing the underlying molecular mechanisms of Notch signal control.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                7 April 2015
                2015
                : 10
                : 4
                : e0123016
                Affiliations
                [1 ]Faculty of Life Sciences, Manchester Institute of Biotechnology (MIB), University of Manchester, Manchester, United Kingdom
                [2 ]Department of Paediatric Haematology, Great Ormond Street Hospital (GOSH), London, United Kingdom
                [3 ]Institute of Inflammation and Repair, Manchester Institute of Biotechnology (MIB), University of Manchester, Manchester, United Kingdom
                Università degli Studi di Firenze, ITALY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: AA AMB. Performed the experiments: AA AMB. Analyzed the data: FS. Wrote the paper: FS. Collected the data: AA AMB. Designed and performed the microarray datasets from GSE database system, wrote the bioinformatics results, and drew the clinical correlation conclusions from the results: PH Re-plotted the graphs and prepared the figures for publication: FS

                [¤a]

                Current Address: Current address: Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Kingdom of Saudi Arabia

                [¤b]

                Current address: Molecular and Cellular Immunology Section, Department of Infection, Immunity and Inflammation, Institute of Child Health (ICH), University College London (UCL), London, United Kingdom

                Article
                PONE-D-14-04154
                10.1371/journal.pone.0123016
                4388554
                25849484
                07bf0adf-13bd-408f-a6df-f8bd2f56810f
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 27 January 2014
                : 26 February 2015
                Page count
                Figures: 11, Tables: 0, Pages: 26
                Funding
                For this work the funding was provided to A.A. by Ministry of Saudi, Government of Saudi Arabia. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article

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