{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:44:33Z","timestamp":1789433073989,"version":"build-2803163510"},"reference-count":106,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,5,21]],"date-time":"2022-05-21T00:00:00Z","timestamp":1653091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The most recent two decades have seen tremendous progress in the understanding and treatment of chronic myeloid leukemia, a disease defined by the characteristic Philadelphia chromosome and the ensuing BCR::ABL fusion protein. However, the biology of the disease extends beyond the Philadelphia chromosome into a nebulous arena of chromosomal and genetic instability, which makes it a genetically heterogeneous disease. The BCR::ABL oncoprotein creates a fertile backdrop for oxidative damage to the DNA, along with impairment of genetic surveillance and the favoring of imprecise error-prone DNA repair pathways. These factors lead to growing chromosomal instability, manifested as additional chromosomal abnormalities along with other genetic aberrations. This worsens with disease progression to accelerated and blast phase, and modulates responses to tyrosine kinase inhibitors. Treatment options that target the genetic aberrations that mitigate chromosome instability might be a potential area for research in patients with advanced phase CML.<\/jats:p>","DOI":"10.3390\/cancers14102533","type":"journal-article","created":{"date-parts":[[2022,5,21]],"date-time":"2022-05-21T09:18:08Z","timestamp":1653124688000},"page":"2533","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Chromosomal Instability in Chronic Myeloid Leukemia: Mechanistic Insights and Effects"],"prefix":"10.3390","volume":"14","author":[{"given":"Jayastu","family":"Senapati","sequence":"first","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9140-0610","authenticated-orcid":false,"given":"Koji","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/243290a0","article-title":"A New Consistent Chromosomal Abnormality in Chronic Myelogenous Leukaemia identified by Quinacrine Fluorescence and Giemsa Staining","volume":"243","author":"Rowley","year":"1973","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1182\/blood.V71.3.697.697","article-title":"Long-Range Mapping of the Philadelphia Chromosome by Pulsed-Field Gel Electrophoresis","volume":"71","author":"Westbrook","year":"1988","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1056\/NEJM199907153410306","article-title":"The Biology of Chronic Myeloid Leukemia","volume":"341","author":"Faderl","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Lebecque, B., Bourgne, C., Vidal, V., and Berger, M.G. (2021). DNA Methylation and Intra-Clonal Heterogeneity: The Chronic Myeloid Leukemia Model. Cancers, 13.","DOI":"10.3390\/cancers13143587"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.1038\/s41467-021-23097-w","article-title":"Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia","volume":"12","author":"Ochi","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1038\/onc.2012.203","article-title":"Targeting abnormal DNA double-strand break repair in tyrosine kinase inhibitor-resistant chronic myeloid leukemias","volume":"32","author":"Tobin","year":"2013","journal-title":"Oncogene"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"27535","DOI":"10.3390\/ijms161126049","article-title":"DNA Repair\u2014A Double-Edged Sword in the Genomic Stability of Cancer Cells\u2014The Case of Chronic Myeloid Leukemia","volume":"16","author":"Pawlowska","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1038\/leu.2016.143","article-title":"Next-generation sequencing identifies major DNA methylation changes during progression of Ph+ chronic myeloid leukemia","volume":"30","author":"Heller","year":"2016","journal-title":"Leukemia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1002\/1878-0261.12191","article-title":"DNA methylation profiling reveals a pathological signature that contributes to transcriptional defects of CD34(+) CD15(\u2212) cells in early chronic-phase chronic myeloid leukemia","volume":"12","author":"Court","year":"2018","journal-title":"Mol. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.semcancer.2017.07.006","article-title":"Epigenetic dysregulation in chronic myeloid leukaemia: A myriad of mechanisms and therapeutic options","volume":"51","author":"Koschmieder","year":"2018","journal-title":"Semin. Cancer Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1186\/s13045-021-01106-1","article-title":"Impact of frontline treatment approach on outcomes of myeloid blast phase CML","volume":"14","author":"Saxena","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1182\/blood-2010-12-326843","article-title":"Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival","volume":"119","author":"Hamilton","year":"2012","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3336","DOI":"10.1002\/cncr.30197","article-title":"A propensity score matching analysis of dasatinib and nilotinib as a frontline therapy for patients with chronic myeloid leukemia in chronic phase","volume":"122","author":"Takahashi","year":"2016","journal-title":"Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e118","DOI":"10.1016\/S2352-3026(15)00021-6","article-title":"Long-term molecular and cytogenetic response and survival outcomes with imatinib 400 mg, imatinib 800 mg, dasatinib, and nilotinib in patients with chronic-phase chronic myeloid leukaemia: Retrospective analysis of patient data from five clinical trials","volume":"2","author":"Jain","year":"2015","journal-title":"Lancet Haematol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1182\/blood.2020009984","article-title":"A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs","volume":"138","author":"Mauro","year":"2021","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1056\/NEJMoa1609324","article-title":"Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia","volume":"376","author":"Hochhaus","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1038\/s41375-020-01111-2","article-title":"Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis","volume":"35","author":"Kantarjian","year":"2021","journal-title":"Leukemia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1200\/JCO.2015.64.8899","article-title":"Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Na\u00efve Chronic Myeloid Leukemia Patients Trial","volume":"34","author":"Cortes","year":"2016","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1200\/JCO.2017.74.7162","article-title":"Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial","volume":"36","author":"Cortes","year":"2018","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e186","DOI":"10.1016\/S2352-3026(15)00048-4","article-title":"Relative survival in patients with chronic-phase chronic myeloid leukaemia in the tyrosine-kinase inhibitor era: Analysis of patient data from six prospective clinical trials","volume":"2","author":"Sasaki","year":"2015","journal-title":"Lancet Haematol."},{"key":"ref_21","first-page":"85","article-title":"Chromosome Studies on Normal and Leukemic Human Leukocytes","volume":"25","author":"Nowell","year":"1960","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1002\/ajh.24943","article-title":"Prognostic significance of additional chromosomal abnormalities at the time of diagnosis in patients with chronic myeloid leukemia treated with frontline tyrosine kinase inhibitors","volume":"93","author":"Alhuraiji","year":"2018","journal-title":"Am. J. Hematol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"88","DOI":"10.3389\/fonc.2019.00088","article-title":"Impact of Additional Chromosomal Aberrations on the Disease Progression of Chronic Myelogenous Leukemia","volume":"9","author":"Chandran","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2742","DOI":"10.1182\/blood-2016-01-690230","article-title":"Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy","volume":"127","author":"Wang","year":"2016","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1182\/bloodadvances.2020003570","article-title":"Additional chromosomal abnormalities at chronic myeloid leukemia diagnosis predict an increased risk of progression","volume":"5","author":"Clark","year":"2021","journal-title":"Blood Adv."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1007\/s12185-021-03127-5","article-title":"Current status and novel strategy of CML","volume":"113","author":"Morita","year":"2021","journal-title":"Int. J. Hematol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.clml.2020.12.025","article-title":"Clinical Outcomes of Patients With Chronic Myeloid Leukemia With Concurrent Core Binding Factor Rearrangement and Philadelphia Chromosome","volume":"21","author":"Morita","year":"2021","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1182\/blood-2017-07-792143","article-title":"Clonal chromosomal abnormalities appearing in Philadelphia chromosome-negative metaphases during CML treatment","volume":"130","author":"Issa","year":"2017","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2641","DOI":"10.1002\/cncr.33539","article-title":"Outcome of patients with chronic myeloid leukemia in lymphoid blastic phase and Philadelphia chromosome-positive acute lymphoblastic leukemia treated with hyper-CVAD and dasatinib","volume":"127","author":"Morita","year":"2021","journal-title":"Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4391","DOI":"10.1002\/cncr.30864","article-title":"Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients","volume":"123","author":"Jain","year":"2017","journal-title":"Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1111\/bjh.13936","article-title":"Analysis of 2013 European LeukaemiaNet (ELN) responses in chronic phase CML across four frontline TKI modalities and impact on clinical outcomes","volume":"173","author":"Jain","year":"2016","journal-title":"Br. J. Haematol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1182\/blood-2015-10-674242","article-title":"Impact of BCR-ABL transcript type on outcome in patients with chronic-phase CML treated with tyrosine kinase inhibitors","volume":"127","author":"Jain","year":"2016","journal-title":"Blood"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/leu.2008.308","article-title":"BCR\/ABL induces chromosomal instability after genotoxic stress and alters the cell death threshold","volume":"23","author":"Dierov","year":"2009","journal-title":"Leukemia"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4253","DOI":"10.1182\/blood-2011-10-385658","article-title":"Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors","volume":"119","author":"Kopinski","year":"2012","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Popp, H.D., Kohl, V., Naumann, N., Flach, J., Brendel, S., Kleiner, H., Weiss, C., Seifarth, W., Saussele, S., and Hofmann, W.-K. (2020). DNA Damage and DNA Damage Response in Chronic Myeloid Leukemia. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041177"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4175","DOI":"10.1182\/blood-2012-11-466938","article-title":"Genomic instability may originate from imatinib-refractory chronic myeloid leukemia stem cells","volume":"121","author":"Schemionek","year":"2013","journal-title":"Blood"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.1172\/JCI41246","article-title":"Chronic myeloid leukemia: Mechanisms of blastic transformation","volume":"120","author":"Perrotti","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.1002\/cncr.25015","article-title":"Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy","volume":"116","author":"Verma","year":"2010","journal-title":"Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/sj.leu.2402813","article-title":"Occurrence of additional chromosome aberrations in chronic myeloid leukemia patients treated with imatinib mesylate","volume":"17","author":"Schoch","year":"2003","journal-title":"Leukemia"},{"key":"ref_40","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_41","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1182\/blood-2016-03-643544","article-title":"The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia","volume":"127","author":"Arber","year":"2016","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1182\/blood-2016-09-696013","article-title":"The chronic myeloid leukemia stem cell: Stemming the tide of persistence","volume":"129","author":"Holyoake","year":"2017","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Soverini, S., De Santis, S., Monaldi, C., Bruno, S., and Mancini, M. (2021). Targeting Leukemic Stem Cells in Chronic Myeloid Leukemia: Is It Worth the Effort?. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22137093"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6760","DOI":"10.1182\/blood-2011-08-373902","article-title":"Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: Long-term observation of 1151 patients from the randomized CML Study IV","volume":"118","author":"Fabarius","year":"2011","journal-title":"Blood"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1182\/blood-2013-05-501569","article-title":"European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013","volume":"122","author":"Baccarani","year":"2013","journal-title":"Blood"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1182\/hematology.2020000108","article-title":"First-generation vs second-generation tyrosine kinase inhibitors: Which is best at diagnosis of chronic phase chronic myeloid leukemia?","volume":"2020","author":"Oehler","year":"2020","journal-title":"Hematol. Am Soc Hematol Educ Program"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"582","DOI":"10.3324\/haematol.2009.014712","article-title":"Impact of additional chromosomal aberrations and BCR-ABL kinase domain mutations on the response to nilotinib in Philadelphia chromosome-positive chronic myeloid leukemia","volume":"95","author":"Kim","year":"2010","journal-title":"Haematologica"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1182\/bloodadvances.2017011858","article-title":"Cytogenetics-based risk prediction of blastic transformation of chronic myeloid leukemia in the era of TKI therapy","volume":"1","author":"Gong","year":"2017","journal-title":"Blood Adv."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"285","DOI":"10.4236\/jct.2016.74030","article-title":"Characterization of Genomic Events Other than Ph and Evaluation of Prognostic Influence on Imatinib in Chronic Myeloid Leukemia (CML): A Study on 1449 Patients from India","volume":"7","author":"Amare","year":"2016","journal-title":"J. Cancer Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1038\/leu.2016.6","article-title":"Differential impact of additional chromosomal abnormalities in myeloid vs lymphoid blast phase of chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy","volume":"30","author":"Chen","year":"2016","journal-title":"Leukemia"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2474","DOI":"10.3109\/10428194.2012.696313","article-title":"Chronic myeloid leukemia stem cells display alterations in expression of genes involved in oxidative phosphorylation","volume":"53","author":"Flis","year":"2012","journal-title":"Leuk. Lymphoma"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2416","DOI":"10.1038\/leu.2014.249","article-title":"AKT-induced reactive oxygen species generate imatinib-resistant clones emerging from chronic myeloid leukemia progenitor cells","volume":"28","author":"Flis","year":"2014","journal-title":"Leukemia"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1182\/blood-2004-03-0849","article-title":"Activation of the PI3K\/mTOR pathway by BCR-ABL contributes to increased production of reactive oxygen species","volume":"105","author":"Kim","year":"2005","journal-title":"Blood"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2008.03.036","article-title":"Genomic instability in myeloid malignancies: Increased reactive oxygen species (ROS), DNA double strand breaks (DSBs) and error-prone repair","volume":"270","author":"Sallmyr","year":"2008","journal-title":"Cancer Lett."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"5816","DOI":"10.1182\/blood-2011-01-326025","article-title":"Do reactive oxygen species play a role in myeloid leukemias?","volume":"117","author":"Hole","year":"2011","journal-title":"Blood"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Trombetti, S., Cesaro, E., Catapano, R., Sessa, R., Lo Bianco, A., Izzo, P., and Grosso, M. (2021). Oxidative Stress and ROS-Mediated Signaling in Leukemia: Novel Promising Perspectives to Eradicate Chemoresistant Cells in Myeloid Leukemia. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052470"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1182\/blood-2005-07-2815","article-title":"BCR\/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance","volume":"108","author":"Koptyra","year":"2006","journal-title":"Blood"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/S1535-6108(04)00056-X","article-title":"BCR\/ABL translocates to the nucleus and disrupts an ATR-dependent intra-S phase checkpoint","volume":"5","author":"Dierov","year":"2004","journal-title":"Cancer Cell"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1038\/387520a0","article-title":"Interaction between ATM protein and c-Abl in response to DNA damage","volume":"387","author":"Shafman","year":"1997","journal-title":"Nature"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3292","DOI":"10.1128\/MCB.22.10.3292-3300.2002","article-title":"c-Abl tyrosine kinase regulates the human Rad9 checkpoint protein in response to DNA damage","volume":"22","author":"Yoshida","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1158\/1535-7163.MCT-09-0936","article-title":"Expression of oncogenic kinase Bcr-Abl impairs mitotic checkpoint and promotes aberrant divisions and resistance to microtubule-targeting agents","volume":"9","author":"Wolanin","year":"2010","journal-title":"Mol. Cancer Ther."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Stetka, J., Gursky, J., Li\u00f1an Velasquez, J., Mojzikova, R., Vyhlidalova, P., Vrablova, L., Bartek, J., and Divoky, V. (2020). Role of DNA Damage Response in Suppressing Malignant Progression of Chronic Myeloid Leukemia and Polycythemia Vera: Impact of Different Oncogenes. Cancers, 12.","DOI":"10.3390\/cancers12040903"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1056\/NEJMoa0804953","article-title":"Inhibition of the Bcl-xL Deamidation Pathway in Myeloproliferative Disorders","volume":"359","author":"Zhao","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/nature10760","article-title":"The DNA damage response and cancer therapy","volume":"481","author":"Lord","year":"2012","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"24","DOI":"10.3389\/fmolb.2020.00024","article-title":"Studying DNA Double-Strand Break Repair: An Ever-Growing Toolbox","volume":"7","author":"Huertas","year":"2020","journal-title":"Front. Mol. Biosci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"6884","DOI":"10.1158\/0008-5472.CAN-08-1101","article-title":"BCR\/ABL and other kinases from chronic myeloproliferative disorders stimulate single-strand annealing, an unfaithful DNA double-strand break repair","volume":"68","author":"Cramer","year":"2008","journal-title":"Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.dnarep.2014.02.008","article-title":"Nonhomologous end joining: A good solution for bad ends","volume":"17","author":"Waters","year":"2014","journal-title":"DNA Repair."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1182\/blood.V110.11.1016.1016","article-title":"Up-Regulated WRN and DNA Ligase III\u03b1 Are Involved in Alternative NHEJ Repair Pathway of DNA Double Strand Breaks (DSB) in Chronic Myeloid Leukemia (CML)","volume":"110","author":"Sallmyr","year":"2007","journal-title":"Blood"},{"key":"ref_69","first-page":"470","article-title":"Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma","volume":"13","author":"Newman","year":"2015","journal-title":"Cell Growth Differ."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Caracciolo, D., Riillo, C., Di Martino, M.T., Tagliaferri, P., and Tassone, P. (2021). Alternative Non-Homologous End-Joining: Error-Prone DNA Repair as Cancer\u2019s Achilles\u2019 Heel. Cancers, 13.","DOI":"10.3390\/cancers13061392"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/carcin\/bgq216","article-title":"BCR-ABL stimulates mutagenic homologous DNA double-strand break repair via the DNA-end-processing factor CtIP","volume":"32","author":"Salles","year":"2011","journal-title":"Carcinogenesis"},{"key":"ref_72","first-page":"699","article-title":"c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors, LIG3 and PARP1, in Tyrosine Kinase\u2013Activated Leukemias","volume":"13","author":"Muvarak","year":"2015","journal-title":"Cell Growth Differ."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3208","DOI":"10.1038\/s41419-017-0004-9","article-title":"Alternative NHEJ pathway proteins as components of MYCN oncogenic activity in human neural crest stem cell differentiation: Implications for neuroblastoma initiation","volume":"8","author":"Newman","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"6187","DOI":"10.1182\/blood-2011-05-352252","article-title":"Chronic myelogenous leukemia stem and progenitor cells demonstrate chromosomal instability related to repeated breakage-fusion-bridge cycles mediated by increased nonhomologous end joining","volume":"119","author":"Chakraborty","year":"2012","journal-title":"Blood"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"5546","DOI":"10.1073\/pnas.1220977110","article-title":"An algorithmic approach for breakage-fusion-bridge detection in tumor genomes","volume":"110","author":"Zakov","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"12683","DOI":"10.1073\/pnas.211357798","article-title":"Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors","volume":"98","author":"Gisselsson","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s40164-021-00242-1","article-title":"Involvement of classic and alternative non-homologous end joining pathways in hematologic malignancies: Targeting strategies for treatment","volume":"10","author":"Valikhani","year":"2021","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/s41571-018-0114-z","article-title":"State-of-the-art strategies for targeting the DNA damage response in cancer","volume":"16","author":"Tang","year":"2019","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/s41392-020-00214-7","article-title":"Centrosome dysfunction: A link between senescence and tumor immunity","volume":"5","author":"Wu","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"E6321","DOI":"10.1073\/pnas.1519388112","article-title":"Chronic centrosome amplification without tumorigenesis","volume":"112","author":"Vitre","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1038\/sj.leu.2403779","article-title":"Centrosome aberrations in chronic myeloid leukemia correlate with stage of disease and chromosomal instability","volume":"19","author":"Giehl","year":"2005","journal-title":"Leukemia"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1111\/j.1600-0609.2010.01459.x","article-title":"Detection of centrosome aberrations in disease-unrelated cells from patients with tumor treated with tyrosine kinase inhibitors","volume":"85","author":"Giehl","year":"2010","journal-title":"Eur. J. Haematol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.3324\/haematol.12793","article-title":"Centrosome aberrations and G1 phase arrest after in vitro and in vivo treatment with the SRC\/ABL inhibitor dasatinib","volume":"93","author":"Fabarius","year":"2008","journal-title":"Haematologica"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Haa\u00df, W., Kleiner, H., Wei\u00df, C., Haferlach, C., Schlegelberger, B., M\u00fcller, 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_85","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_86","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.3109\/10428194.2013.845883","article-title":"Potential mechanisms of disease progression and management of advanced-phase chronic myeloid leukemia","volume":"55","author":"Jabbour","year":"2014","journal-title":"Leuk. Lymphoma"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Alves, R., Gon\u00e7alves, A.C., Rutella, S., Almeida, A.M., De Las Rivas, J., Trougakos, I.P., and Ribeiro, A.B.S. (2021). Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia-From Molecular Mechanisms to Clinical Relevance. Cancers, 13.","DOI":"10.3390\/cancers13194820"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Bavaro, L., Martelli, M., Cavo, M., and Soverini, S. (2019). Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20246141"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1159\/000513925","article-title":"Two Cases of Possible Familial Chronic Myeloid Leukemia in a Family with Extensive History of Cancer","volume":"144","author":"Aitken","year":"2021","journal-title":"Acta Haematol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1182\/blood-2013-02-485573","article-title":"JAK of all trades: JAK2-STAT5 as novel therapeutic targets in BCR-ABL1+ chronic myeloid leukemia","volume":"122","author":"Warsch","year":"2013","journal-title":"Blood"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Kurosu, T., Nagao, T., Wu, N., Oshikawa, G., and Miura, O. (2013). Inhibition of the PI3K\/Akt\/GSK3 Pathway Downstream of BCR\/ABL, Jak2-V617F, or FLT3-ITD Downregulates DNA Damage-Induced Chk1 Activation as Well as G2\/M Arrest and Prominently Enhances Induction of Apoptosis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0079478"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Amarante-Mendes, G.P., Rana, A., Datoguia, T.S., Hamerschlak, N., and Brumatti, G. (2022). BCR-ABL1 Tyrosine Kinase Complex Signaling Transduction: Challenges to Overcome Resistance in Chronic Myeloid Leukemia. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14010215"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.cancergen.2012.08.004","article-title":"Acquired genomic copy number changes in CML patients with the Philadelphia chromosome (Ph+)","volume":"205","author":"Lu","year":"2012","journal-title":"Cancer Genet."},{"key":"ref_94","first-page":"1471","article-title":"Genomic Copy Number Variants in CML Patients with the Philadelphia Chromosome (Ph+): An Update","volume":"12","author":"Zhang","year":"2021","journal-title":"Front. Genet."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/S0165-4608(98)00213-1","article-title":"Comparative Analysis of G-Banding, Chromosome Painting, Locus-Specific Fluorescence In Situ Hybridization, and Comparative Genomic Hybridization in Chronic Myeloid Leukemia Blast Crisis","volume":"111","author":"Gribble","year":"1999","journal-title":"Cancer Genet. Cytogenet."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"471","DOI":"10.2174\/138920212802510466","article-title":"On the Power of Additional and Complex Chromosomal Aberrations in CML","volume":"13","author":"Heinze","year":"2012","journal-title":"Curr Genom."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1159\/000506346","article-title":"Venetoclax and BCR-ABL Tyrosine Kinase Inhibitor Combinations: Outcome in Patients with Philadelphia Chromosome-Positive Advanced Myeloid Leukemias","volume":"143","author":"Maiti","year":"2020","journal-title":"Acta Haematol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1182\/bloodadvances.2018025874","article-title":"Analysis of cardiovascular and arteriothrombotic adverse events in chronic-phase CML patients after frontline TKIs","volume":"3","author":"Jain","year":"2019","journal-title":"Blood Adv."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s12185-019-02620-2","article-title":"Incidence of second malignancies in patients with chronic myeloid leukemia in the era of tyrosine kinase inhibitors","volume":"109","author":"Sasaki","year":"2019","journal-title":"Int. J. Hematol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1002\/cncr.29745","article-title":"Conditional survival in patients with chronic myeloid leukemia in chronic phase in the era of tyrosine kinase inhibitors","volume":"122","author":"Sasaki","year":"2016","journal-title":"Cancer"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.clml.2015.12.003","article-title":"Clinical Safety and Efficacy of Nilotinib or Dasatinib in Patients with Newly Diagnosed Chronic-Phase Chronic Myelogenous Leukemia and Pre-Existing Liver and\/or Renal Dysfunction","volume":"16","author":"Sasaki","year":"2016","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1002\/ajh.26047","article-title":"The LEukemia Artificial Intelligence Program (LEAP) in chronic myeloid leukemia in chronic phase: A model to improve patient outcomes","volume":"96","author":"Sasaki","year":"2021","journal-title":"Am. J. Hematol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2853","DOI":"10.3324\/haematol.2020.260125","article-title":"The effect of eltrombopag in managing thrombocytopenia associated with tyrosine kinase therapy in patients with chronic myeloid leukemia and myelofibrosis","volume":"106","author":"Shoukier","year":"2021","journal-title":"Haematologica"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1182\/blood-2021-154380","article-title":"Treatment-free remission in patients with chronic myeloid leukemia following the discontinuation of tyrosine kinase inhibitors","volume":"138","author":"Haddad","year":"2021","journal-title":"Blood"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1111\/bjh.16245","article-title":"Sudden blastic transformation in treatment-free remission chronic myeloid leukaemia","volume":"187","author":"Alfayez","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_106","first-page":"1179","article-title":"Chronic myeloid leukemia: Update on treatment and survival prediction","volume":"61","author":"Sasaki","year":"2020","journal-title":"Jpn. J. Clin. Hematol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/10\/2533\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:15:59Z","timestamp":1760138159000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/10\/2533"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,21]]},"references-count":106,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["cancers14102533"],"URL":"https:\/\/doi.org\/10.3390\/cancers14102533","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,21]]}}}