{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T15:10:00Z","timestamp":1782918600491,"version":"3.54.5"},"reference-count":47,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T00:00:00Z","timestamp":1683504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005677","name":"Deutsche Jos\u00e9 Carreras Leuk\u00e4mie-Stiftung","doi-asserted-by":"publisher","award":["13R\/2017"],"award-info":[{"award-number":["13R\/2017"]}],"id":[{"id":"10.13039\/501100005677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005677","name":"Deutsche Jos\u00e9 Carreras Leuk\u00e4mie-Stiftung","doi-asserted-by":"publisher","award":["2019.021.1"],"award-info":[{"award-number":["2019.021.1"]}],"id":[{"id":"10.13039\/501100005677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008672","name":"Wilhelm Sander-Stiftung","doi-asserted-by":"publisher","award":["13R\/2017"],"award-info":[{"award-number":["13R\/2017"]}],"id":[{"id":"10.13039\/100008672","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008672","name":"Wilhelm Sander-Stiftung","doi-asserted-by":"publisher","award":["2019.021.1"],"award-info":[{"award-number":["2019.021.1"]}],"id":[{"id":"10.13039\/100008672","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The achievement of major molecular response (MMR, BCR::ABL1 \u2264 0.1% IS) within the first year of treatment with tyrosine kinase inhibitors (TKI) is a milestone in the therapeutic management of patients with newly diagnosed chronic myeloid leukemia (CML). We analyzed the predictive value of gene expression levels of ESPL1\/Separase, PTTG1\/Securin and PTTG1IP\/Securin interacting protein for MMR achievement within 12 months. Relative expression levels (normalized to GUSB) of ESPL1, PTTG1 and PTTG1IP in white blood cells of patients (responders n = 46, non-responders n = 51) at the time of diagnosis were comparatively analyzed by qRT-PCR. 3D scatter plot analysis combined with a distance analysis performed with respect to a commonly calculated centroid center resulted in a trend to larger distances for non-responders compared to the responder cohort (p = 0.0187). Logistic regression and analysis of maximum likelihood estimates revealed a positive correlation of distance (cut-off) with non-achieving MMR within 12 months (p = 0.0388, odds ratio 1.479, 95%CI: 1.020 to 2.143). Thus, 10% of the tested non-responders (cut-off \u2265 5.9) could have been predicted already at the time of diagnosis. Future scoring of ESPL1, PTTG1 and PTTG1IP transcript levels may be a helpful tool in risk stratification of CML patients before initiation of TKI first-line treatment.<\/jats:p>","DOI":"10.3390\/cancers15092652","type":"journal-article","created":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T02:03:31Z","timestamp":1683511411000},"page":"2652","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Gene Expression Pattern of ESPL1, PTTG1 and PTTG1IP Can Potentially Predict Response to TKI First-Line Treatment of Patients with Newly Diagnosed CML"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5268-1934","authenticated-orcid":false,"given":"Eva","family":"Christiani","sequence":"first","affiliation":[{"name":"Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Naumann","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christel","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Medical Statistics and Biomathematics, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Spiess","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helga","family":"Kleiner","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Fabarius","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolf-Karsten","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0357-5785","authenticated-orcid":false,"given":"Susanne","family":"Saussele","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2490-9321","authenticated-orcid":false,"given":"Wolfgang","family":"Seifarth","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2398","DOI":"10.1038\/leu.2017.253","article-title":"Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants","volume":"31","author":"Hehlmann","year":"2017","journal-title":"Leukemia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1038\/s41375-020-0776-2","article-title":"European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia","volume":"34","author":"Hochhaus","year":"2020","journal-title":"Leukemia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3330","DOI":"10.1182\/blood-2008-04-150680","article-title":"Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials","volume":"112","author":"Branford","year":"2008","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.1038\/leu.2012.104","article-title":"Standardized definitions of molecular response in chronic myeloid leukemia","volume":"26","author":"Cross","year":"2012","journal-title":"Leukemia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1038\/leu.2015.29","article-title":"Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia","volume":"29","author":"Cross","year":"2015","journal-title":"Leukemia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.1056\/NEJMoa062867","article-title":"Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia","volume":"355","author":"Druker","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"S141","DOI":"10.1007\/s00277-015-2322-2","article-title":"A review of the European LeukemiaNet recommendations for the management of CML","volume":"94","author":"Baccarani","year":"2015","journal-title":"Ann. Hematol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1002\/cncr.29053","article-title":"Analyzing molecular response in chronic myeloid leukemia clinical trials: Pitfalls and golden rules","volume":"121","author":"Guilhot","year":"2015","journal-title":"Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"80105","DOI":"10.18632\/oncotarget.21049","article-title":"Molecular response prediction in CML: Novel ideas?","volume":"8","author":"Wolf","year":"2017","journal-title":"Oncotarget"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1182\/blood-2014-03-566323","article-title":"Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline","volume":"124","author":"Branford","year":"2014","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.leukres.2016.06.010","article-title":"Early molecular response in chronic myeloid leukemia and halving time: Latest evidences","volume":"48","author":"Breccia","year":"2016","journal-title":"Leuk. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"12330","DOI":"10.1038\/s41598-018-29923-4","article-title":"Quantitative prediction of long-term molecular response in TKI-treated CML\u2014Lessons from an imatinib versus dasatinib comparison","volume":"8","author":"Glauche","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1007\/s00277-020-04007-4","article-title":"Separase activity distribution can be a marker of major molecular response and proliferation of CD34(+) cells in TKI-treated chronic myeloid leukemia patients","volume":"99","author":"Spiess","year":"2020","journal-title":"Ann. Hematol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4574","DOI":"10.1073\/pnas.0730733100","article-title":"Processing, localization, and requirement of human separase for normal anaphase progression","volume":"100","author":"Chestukhin","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1038\/ncb2280","article-title":"Cleavage of cohesin rings coordinates the separation of centrioles and chromatids","volume":"13","author":"Schockel","year":"2011","journal-title":"Nat. Cell. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/2162-3619-3-13","article-title":"Cohesin mutations in myeloid malignancies: Underlying mechanisms","volume":"3","author":"Leeke","year":"2014","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1038\/nature11630","article-title":"Post-replicative repair involves separase-dependent removal of the kleisin subunit of cohesin","volume":"493","author":"McAleenan","year":"2013","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1093\/nar\/gkx1172","article-title":"Separase prevents genomic instability by controlling replication fork speed","volume":"46","author":"Cucco","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e99184","DOI":"10.15252\/embj.201899184","article-title":"Local activation of mammalian separase in interphase promotes double-strand break repair and prevents oncogenic transformation","volume":"37","author":"Hellmuth","year":"2018","journal-title":"EMBO J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"13033","DOI":"10.1073\/pnas.0801610105","article-title":"Overexpression of Separase induces aneuploidy and mammary tumorigenesis","volume":"105","author":"Zhang","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Haass, W., Kleiner, H., Weiss, C., Haferlach, C., Schlegelberger, B., Muller, M.C., Hehlmann, R., Hofmann, W.K., Fabarius, A., and Seifarth, W. (2015). Clonal Evolution and Blast Crisis Correlate with Enhanced Proteolytic Activity of Separase in BCR-ABL b3a2 Fusion Type CML under Imatinib Therapy. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0129648"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Mukherjee, M., Ge, G., Zhang, N., Huang, E., Nakamura, L.V., Minor, M., Fofanov, V., Rao, P.H., Herron, A., and Pati, D. (2011). Separase loss of function cooperates with the loss of p53 in the initiation and progression of T- and B-cell lymphoma, leukemia and aneuploidy in mice. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0022167"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3481","DOI":"10.4161\/cc.7.22.7048","article-title":"Oncogenic activity of separase","volume":"7","author":"Pati","year":"2008","journal-title":"Cell Cycle"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2703","DOI":"10.1158\/1078-0432.CCR-08-2454","article-title":"Overexpression and mislocalization of the chromosomal segregation protein separase in multiple human cancers","volume":"15","author":"Meyer","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1093\/embo-reports\/kve113","article-title":"Secured cutting: Controlling separase at the metaphase to anaphase transition","volume":"2","author":"Uhlmann","year":"2001","journal-title":"EMBO Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1016\/S0960-9822(02)01073-4","article-title":"Regulation of human separase by securin binding and autocleavage","volume":"12","author":"Waizenegger","year":"2002","journal-title":"Curr. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3325","DOI":"10.1242\/jcs.03083","article-title":"Cyclin-B1-mediated inhibition of excess separase is required for timely chromosome disjunction","volume":"119","author":"Holland","year":"2006","journal-title":"J. Cell Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/S0960-9822(02)00847-3","article-title":"The dual mechanism of separase regulation by securin","volume":"12","author":"Hornig","year":"2002","journal-title":"Curr. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1210\/er.2006-0042","article-title":"Pituitary tumor-transforming gene: Physiology and implications for tumorigenesis","volume":"28","author":"Vlotides","year":"2007","journal-title":"Endocr. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Agircan, F.G., and Schiebel, E. (2014). Sensors at centrosomes reveal determinants of local separase activity. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004672"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1530\/ERC-16-0340","article-title":"Functional consequences of the first reported mutations of the proto-oncogene PTTG1IP\/PBF","volume":"24","author":"Imruetaicharoenchoke","year":"2017","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1210\/en.2013-1646","article-title":"The PTTG1-binding factor (PBF\/PTTG1IP) regulates p53 activity in thyroid cells","volume":"155","author":"Read","year":"2014","journal-title":"Endocrinology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"39","DOI":"10.3109\/10428199309047861","article-title":"Minimal residual disease after bone marrow transplant for chronic myeloid leukaemia detected by the polymerase chain reaction","volume":"11","author":"Cross","year":"1993","journal-title":"Leuk. Lymphoma"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1038\/sj.leu.2401566","article-title":"Accurate and rapid analysis of residual disease in patients with CML using specific fluorescent hybridization probes for real time quantitative RT-PCR","volume":"13","author":"Emig","year":"1999","journal-title":"Leukemia"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Spiess, B., Rinaldetti, S., Naumann, N., Galuschek, N., Kossak-Roth, U., Wuchter, P., Tarnopolscaia, I., Rose, D., Voskanyan, A., and Fabarius, A. (2019). Diagnostic performance of the molecular BCR-ABL1 monitoring system may impact on inclusion of CML patients in stopping trials. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0214305"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Yu, H., Wang, L., Chen, D., Li, J., and Guo, Y. (2021). Conditional transcriptional relationships may serve as cancer prognostic markers. BMC Med. Genom., 14.","DOI":"10.1186\/s12920-021-00958-3"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"547","DOI":"10.3892\/or.2016.5226","article-title":"Expression of genes encoding centrosomal proteins and the humoral response against these proteins in chronic myeloid leukemia","volume":"37","author":"Smahelova","year":"2017","journal-title":"Oncol. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Haass, W., Stehle, M., Nittka, S., Giehl, M., Schrotz-King, P., Fabarius, A., Hofmann, W.K., and Seifarth, W. (2012). The proteolytic activity of separase in BCR-ABL-positive cells is increased by imatinib. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042863"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1186\/s13045-015-0209-2","article-title":"PTTG1 expression is associated with hyperproliferative disease and poor prognosis in multiple myeloma","volume":"8","author":"Noll","year":"2015","journal-title":"J. Hematol. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Xu, J., Wang, M., Gao, X., Hu, B., Du, Y., Zhou, J., Tian, X., and Huang, X. (2011). Separase phosphosite mutation leads to genome instability and primordial germ cell depletion during oogenesis. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0018763"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Repo, H., Gurvits, N., Loyttyniemi, E., Nykanen, M., Lintunen, M., Karra, H., Kurki, S., Kuopio, T., Talvinen, K., and Soderstrom, M. (2017). PTTG1-interacting protein (PTTG1IP\/PBF) predicts breast cancer survival. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3694-6"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1111\/ejh.13238","article-title":"Variant-specific discrepancy when quantitating BCR-ABL1 e13a2 and e14a2 transcripts using the Europe Against Cancer qPCR assay","volume":"103","author":"Kjaer","year":"2019","journal-title":"Eur. J. Haematol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1111\/ejh.13282","article-title":"\u201cVariant-specific discrepancy when quantitating BCR-ABL1 e13a2 and e14a2 transcripts using the Europe Against Cancer qPCR assay.\u201d Is dPCR the key?","volume":"103","author":"Bernardi","year":"2019","journal-title":"Eur. J. Haematol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1111\/j.1365-2141.2011.08603.x","article-title":"Guidelines for the measurement of BCR-ABL1 transcripts in chronic myeloid leukaemia","volume":"153","author":"Foroni","year":"2011","journal-title":"Br. J. Haematol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1038\/s41375-022-01607-z","article-title":"Standardization of molecular monitoring of CML: Results and recommendations from the European treatment and outcome study","volume":"36","author":"White","year":"2022","journal-title":"Leukemia"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4439","DOI":"10.1182\/blood-2013-03-490003","article-title":"The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: From the perspective of a large group of CML experts","volume":"121","year":"2013","journal-title":"Blood"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/9\/2652\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:31:04Z","timestamp":1760124664000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/9\/2652"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,8]]},"references-count":47,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["cancers15092652"],"URL":"https:\/\/doi.org\/10.3390\/cancers15092652","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,8]]}}}