{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T11:10:02Z","timestamp":1761217802072},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,7,24]],"date-time":"2015-07-24T00:00:00Z","timestamp":1437696000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,7,24]],"date-time":"2015-07-24T00:00:00Z","timestamp":1437696000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Co-expression analysis reveals useful dysregulation patterns of gene cooperativeness for understanding cancer biology and identifying new targets for treatment. We developed a structural strategy to identify co-expressed gene networks that are important for chronic myelogenous leukemia (CML). This strategy compared the distributions of expressional correlations between CML and normal states and it identified a data-driven threshold to classify strongly co-expressed networks that had the best coherence with CML. Using this strategy, we found a transcriptome-wide reduction of co-expression connectivity in CML, reflecting potentially loosened molecular regulation. Conversely, when we focused on <jats:italic>nucleophosmin 1<\/jats:italic> (<jats:italic>NPM1<\/jats:italic>) associated networks, <jats:italic>NPM1<\/jats:italic> established more co-expression linkages with BCR-ABL pathways and ribosomal protein networks in CML than normal. This finding implicates a new role of <jats:italic>NPM1<\/jats:italic> in conveying tumorigenic signals from the BCR-ABL oncoprotein to ribosome biogenesis, affecting cellular growth. Transcription factors may be regulators of the differential co-expression patterns between CML and normal.<\/jats:p>","DOI":"10.1038\/srep10973","type":"journal-article","created":{"date-parts":[[2015,7,24]],"date-time":"2015-07-24T09:08:59Z","timestamp":1437728939000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Novel structural co-expression analysis linking the NPM1-associated ribosomal biogenesis network to chronic myelogenous leukemia"],"prefix":"10.1038","volume":"5","author":[{"given":"Lawrence WC","family":"Chan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xihong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Godwin","family":"Yung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Lui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya Ming","family":"Chiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fengfeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy BY","family":"Tsui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William CS","family":"Cho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"SP","family":"Yip","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Parco M.","family":"Siu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"SC Cesar","family":"Wong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin YM","family":"Yung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,7,24]]},"reference":[{"key":"BFsrep10973_CR1","doi-asserted-by":"publisher","first-page":"2096","DOI":"10.1093\/bioinformatics\/btm309","volume":"23","author":"LL Elo","year":"2007","unstructured":"Elo, L. L., Jarvenpaa, H., Oresic, M., Lahesmaa, R. & Aittokallio, T. Systematic construction of gene coexpression networks with applications to human T helper cell differentiation process. Bioinformatics 23, 2096\u20132103 (2007).","journal-title":"Bioinformatics"},{"key":"BFsrep10973_CR2","doi-asserted-by":"publisher","first-page":"S233","DOI":"10.1093\/bioinformatics\/18.suppl_1.S233","volume":"18","author":"T Ideker","year":"2002","unstructured":"Ideker, T., Ozier, O., Schwikowski, B. & Siegel, A. F. Discovering regulatory and signalling circuits in molecular interaction networks. Bioinformatics 18 Suppl 1 S233\u2013240 (2002).","journal-title":"Bioinformatics"},{"key":"BFsrep10973_CR3","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1007\/s00335-007-9043-3","volume":"18","author":"TF Fuller","year":"2007","unstructured":"Fuller, T. F. et al. Weighted gene coexpression network analysis strategies applied to mouse weight. Mamm Genome 18, 463\u2013472 (2007).","journal-title":"Mamm Genome"},{"key":"BFsrep10973_CR4","doi-asserted-by":"publisher","first-page":"e1000117","DOI":"10.1371\/journal.pcbi.1000117","volume":"4","author":"S Horvath","year":"2008","unstructured":"Horvath, S. & Dong, J. Geometric interpretation of gene coexpression network analysis. PLoS Comput Biol 4, e1000117 (2008).","journal-title":"PLoS Comput Biol"},{"key":"BFsrep10973_CR5","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1101\/gr.1910904","volume":"14","author":"HK Lee","year":"2004","unstructured":"Lee, H. K., Hsu, A. K., Sajdak, J., Qin, J. & Pavlidis, P. Coexpression analysis of human genes across many microarray data sets. Genome Res 14, 1085\u20131094 (2004).","journal-title":"Genome Res"},{"key":"BFsrep10973_CR6","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","volume":"57","author":"Y Benjamini","year":"1995","unstructured":"Benjamini, Y. & Hochberg, Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society. Series B (Methodological) 57, 289\u2013300 (1995).","journal-title":"Series B (Methodological)"},{"key":"BFsrep10973_CR7","doi-asserted-by":"publisher","first-page":"9440","DOI":"10.1073\/pnas.1530509100","volume":"100","author":"JD Storey","year":"2003","unstructured":"Storey, J. D. & Tibshirani, R. Statistical significance for genomewide studies. Proc Natl Acad Sci USA 100, 9440\u20139445 (2003).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep10973_CR8","doi-asserted-by":"publisher","first-page":"2780","DOI":"10.1093\/bioinformatics\/btp502","volume":"25","author":"Y Choi","year":"2009","unstructured":"Choi, Y. & Kendziorski, C. Statistical methods for gene set co-expression analysis. Bioinformatics 25, 2780\u20132786 (2009).","journal-title":"Bioinformatics"},{"key":"BFsrep10973_CR9","doi-asserted-by":"publisher","first-page":"e1000382","DOI":"10.1371\/journal.pcbi.1000382","volume":"5","author":"NJ Hudson","year":"2009","unstructured":"Hudson, N. J., Reverter, A. & Dalrymple, B. P. A differential wiring analysis of expression data correctly identifies the gene containing the causal mutation. PLoS Comput Biol 5, e1000382 (2009).","journal-title":"PLoS Comput Biol"},{"key":"BFsrep10973_CR10","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1158\/1078-0432.CCR-10-1613","volume":"18","author":"D Cilloni","year":"2012","unstructured":"Cilloni, D. & Saglio, G. Molecular pathways: BCR-ABL. Clin Cancer Res 18, 930\u2013937 (2012).","journal-title":"Clin Cancer Res"},{"key":"BFsrep10973_CR11","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/nrc1885","volume":"6","author":"S Grisendi","year":"2006","unstructured":"Grisendi, S., Mecucci, C., Falini, B. & Pandolfi, P. P. Nucleophosmin and cancer. Nat Rev Cancer 6, 493\u2013505 (2006).","journal-title":"Nat Rev Cancer"},{"key":"BFsrep10973_CR12","doi-asserted-by":"publisher","first-page":"1821","DOI":"10.1038\/onc.2009.473","volume":"29","author":"Z Yao","year":"2010","unstructured":"Yao, Z. et al. B23 acts as a nucleolar stress sensor and promotes cell survival through its dynamic interaction with hnRNPU and hnRNPA1. Oncogene 29, 1821\u20131834 (2010).","journal-title":"Oncogene"},{"key":"BFsrep10973_CR13","doi-asserted-by":"publisher","first-page":"1609","DOI":"10.1158\/0008-5472.CAN-06-2875","volume":"67","author":"CL Pelletier","year":"2007","unstructured":"Pelletier, C. L. et al. TSC1 sets the rate of ribosome export and protein synthesis through nucleophosmin translation. Cancer Res 67, 1609\u20131617 (2007).","journal-title":"Cancer Res"},{"key":"BFsrep10973_CR14","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2005","unstructured":"Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102, 15545\u201315550 (2005).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep10973_CR15","doi-asserted-by":"publisher","first-page":"D122","DOI":"10.1093\/nar\/gkl879","volume":"35","author":"V Ferretti","year":"2007","unstructured":"Ferretti, V. et al. PReMod: a database of genome-wide mammalian cis-regulatory module predictions. Nucleic Acids Res 35, D122\u2013126 (2007).","journal-title":"Nucleic Acids Res"},{"key":"BFsrep10973_CR16","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1038\/sj.leu.2404549","volume":"21","author":"E Diaz-Blanco","year":"2007","unstructured":"Diaz-Blanco, E. et al. Molecular signature of CD34(+) hematopoietic stem and progenitor cells of patients with CML in chronic phase. Leukemia 21, 494\u2013504 (2007).","journal-title":"Leukemia"},{"key":"BFsrep10973_CR17","doi-asserted-by":"publisher","first-page":"S96","DOI":"10.1093\/bioinformatics\/18.suppl_1.S96","volume":"18","author":"W Huber","year":"2002","unstructured":"Huber, W., von Heydebreck, A., Sultmann, H., Poustka, A. & Vingron, M. Variance stabilization applied to microarray data calibration and to the quantification of differential expression. Bioinformatics 18, S96\u2013S104 (2002).","journal-title":"Bioinformatics"},{"key":"BFsrep10973_CR18","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.fob.2012.04.003","volume":"2","author":"H Araki","year":"2012","unstructured":"Araki, H., Knapp, C., Tsai, P. & Print, C. GeneSetDB: A comprehensive meta-database, statistical and visualisation framework for gene set analysis. FEBS Open Bio 2, 76\u201382 (2012).","journal-title":"FEBS Open Bio"},{"key":"BFsrep10973_CR19","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/75556","volume":"25","author":"M Ashburner","year":"2000","unstructured":"Ashburner, M. et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25, 25\u201329 (2000).","journal-title":"Nat Genet"},{"key":"BFsrep10973_CR20","doi-asserted-by":"publisher","first-page":"D691","DOI":"10.1093\/nar\/gkq1018","volume":"39","author":"D Croft","year":"2011","unstructured":"Croft, D. et al. Reactome: a database of reactions, pathways and biological processes. Nucleic Acids Res 39, D691\u2013697 (2011).","journal-title":"Nucleic Acids Res"},{"key":"BFsrep10973_CR21","doi-asserted-by":"publisher","first-page":"2473","DOI":"10.1093\/bioinformatics\/btp462","volume":"25","author":"A Marco","year":"2009","unstructured":"Marco, A., Konikoff, C., Karr, T. L. & Kumar, S. Relationship between gene co-expression and sharing of transcription factor binding sites in Drosophila melanogaster. Bioinformatics 25, 2473\u20132477 (2009).","journal-title":"Bioinformatics"},{"key":"BFsrep10973_CR22","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.cbi.2008.11.015","volume":"179","author":"A Bishayee","year":"2009","unstructured":"Bishayee, A. & Dhir, N. Resveratrol-mediated chemoprevention of diethylnitrosamine-initiated hepatocarcinogenesis: inhibition of cell proliferation and induction of apoptosis. Chem Biol Interact 179, 131\u2013144 (2009).","journal-title":"Chem Biol Interact"},{"key":"BFsrep10973_CR23","first-page":"225","volume":"2","author":"BJ Druker","year":"2003","unstructured":"Druker, B. J. Overcoming resistance to imatinib by combining targeted agents. Mol Cancer Ther 2, 225\u2013226 (2003).","journal-title":"Mol Cancer Ther"},{"key":"BFsrep10973_CR24","doi-asserted-by":"publisher","first-page":"16039","DOI":"10.1074\/jbc.M110.204057","volume":"286","author":"KJ Dery","year":"2011","unstructured":"Dery, K. J. et al. Mechanistic control of carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) splice isoforms by the heterogeneous nuclear ribonuclear proteins hnRNP L, hnRNP A1 and hnRNP M. J Biol Chem 286, 16039\u201316051 (2011).","journal-title":"J Biol Chem"},{"key":"BFsrep10973_CR25","doi-asserted-by":"publisher","first-page":"7050","DOI":"10.1128\/MCB.01548-07","volume":"28","author":"LB Maggi Jr.","year":"2008","unstructured":"Maggi, L. B., Jr. et al. Nucleophosmin serves as a rate-limiting nuclear export chaperone for the Mammalian ribosome. Mol Cell Biol 28, 7050\u20137065 (2008).","journal-title":"Mol Cell Biol"},{"key":"BFsrep10973_CR26","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1038\/nmeth.1226","volume":"5","author":"A Mortazavi","year":"2008","unstructured":"Mortazavi, A., Williams, B. A., McCue, K., Schaeffer, L. & Wold, B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods 5, 621\u2013628 (2008).","journal-title":"Nat Methods"},{"key":"BFsrep10973_CR27","unstructured":"Pearson, E. S. & Hartley, H. O. Biometrika Tables for Statisticians. Vol. 2 (Cambridge University Press, 1972)."},{"key":"BFsrep10973_CR28","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1007\/s00787-010-0087-7","volume":"19","author":"M Szumilas","year":"2010","unstructured":"Szumilas, M. Explaining odds ratios. J Can Acad Child Adolesc Psychiatry 19, 227\u2013229 (2010).","journal-title":"J Can Acad Child Adolesc Psychiatry"},{"key":"BFsrep10973_CR29","doi-asserted-by":"publisher","first-page":"13418","DOI":"10.1073\/pnas.1233632100","volume":"100","author":"H Brentani","year":"2003","unstructured":"Brentani, H. et al. The generation and utilization of a cancer-oriented representation of the human transcriptome by using expressed sequence tags. Proc Natl Acad Sci USA 100, 13418\u201313423 (2003).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep10973_CR30","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1111\/j.2517-6161.1953.tb00135.x","volume":"15","author":"H Hotelling","year":"1953","unstructured":"Hotelling, H. New Light on the Correlation Coefficient and its Transforms. Journal of the Royal Statistical Society. Series B (Methodological) 15, 193\u2013232 (1953).","journal-title":"Series B (Methodological)"},{"key":"BFsrep10973_CR31","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1111\/1467-9868.00346","volume":"64","author":"JD Storey","year":"2002","unstructured":"Storey, J. D. A direct approach to false discovery rates. Journal of the Royal Statistical Society. Series B (Statistical Methodology) 64, 479\u2013498 (2002).","journal-title":"Series B (Statistical Methodology)"},{"key":"BFsrep10973_CR32","doi-asserted-by":"publisher","first-page":"e52127","DOI":"10.1371\/journal.pone.0052127","volume":"7","author":"AN Tegge","year":"2012","unstructured":"Tegge, A. N., Caldwell, C. W. & Xu, D. Pathway Correlation Profile of Gene-Gene Co-Expression for Identifying Pathway Perturbation. PLoS ONE 7, e52127 (2012).","journal-title":"PLoS ONE"},{"key":"BFsrep10973_CR33","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/1475-2867-12-47","volume":"12","author":"AM Osman","year":"2012","unstructured":"Osman, A. M., Bayoumi, H. M., Al-Harthi, S. E., Damanhouri, Z. A. & Elshal, M. F. Modulation of doxorubicin cytotoxicity by resveratrol in a human breast cancer cell line. Cancer Cell Int 12, 47 (2012).","journal-title":"Cancer Cell Int"},{"key":"BFsrep10973_CR34","first-page":"2673","volume":"32","author":"G Can","year":"2012","unstructured":"Can, G., Cakir, Z., Kartal, M., Gunduz, U. & Baran, Y. Apoptotic effects of resveratrol, a grape polyphenol, on imatinib-sensitive and resistant K562 chronic myeloid leukemia cells. Anticancer Res 32, 2673\u20132678 (2012).","journal-title":"Anticancer Res"},{"key":"BFsrep10973_CR35","doi-asserted-by":"publisher","first-page":"87","DOI":"10.2307\/2340521","volume":"85","author":"RA Fisher","year":"1922","unstructured":"Fisher, R. A. On the interpretation of \u03c72 from contingency tables and the calculation of P. J. R. Stat. Soc. 85, 87\u201394 (1922).","journal-title":"J. R. Stat. Soc"},{"key":"BFsrep10973_CR36","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1037\/a0024223","volume":"96","author":"DA Biddle","year":"2011","unstructured":"Biddle, D. A. & Morris, S. B. Using Lancaster\u2019s mid-P correction to the Fisher\u2019s exact test for adverse impact analyses. J Appl Psychol 96, 956\u2013965 (2011).","journal-title":"J Appl Psychol"},{"key":"BFsrep10973_CR37","first-page":"395","volume":"155","author":"GJ Upton","year":"1992","unstructured":"Upton, G. J. Fisher\u2019s exact test. J. Appl. Psychol. 155, 395\u2013402 (1992).","journal-title":"J. Appl. Psychol."},{"key":"BFsrep10973_CR38","first-page":"3","volume":"8","author":"CE Bonferroni","year":"1936","unstructured":"Bonferroni, C. E. Teoria statistica delle classi e calcolo delle probabilit\u00e0. Pubblicazioni del R Istituto Superiore di Scienze Economiche e Commerciali di Firenze 8, 3\u201362 (1936).","journal-title":"Pubblicazioni del R Istituto Superiore di Scienze Economiche e Commerciali di Firenze"},{"key":"BFsrep10973_CR39","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1016\/S0168-9525(03)00175-6","volume":"19","author":"H Yu","year":"2003","unstructured":"Yu, H., Luscombe, N. M., Qian, J. & Gerstein, M. Genomic analysis of gene expression relationships in transcriptional regulatory networks. Trends Genet 19, 422\u2013427 (2003).","journal-title":"Trends Genet"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep10973","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep10973.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep10973.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T23:11:00Z","timestamp":1672960260000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep10973"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,7,24]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,9,1]]}},"alternative-id":["BFsrep10973"],"URL":"https:\/\/doi.org\/10.1038\/srep10973","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,7,24]]},"assertion":[{"value":"11 January 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 May 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 July 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"10973"}}