{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:56:00Z","timestamp":1791860160433,"version":"4.3.4"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T00:00:00Z","timestamp":1703203200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["por-journal.com"],"crossmark-restriction":true},"short-container-title":["Pathol. Oncol. Res."],"abstract":"<jats:p><jats:bold>Objective:<\/jats:bold> BCR-ABL1 kinase domain (KD) mutations can lead to resistance to first- and second-generation tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Here, we present the first report of the spectrum of mutations in the BCR-ABL1 KD of CML patients from Azerbaijan.<\/jats:p><jats:p><jats:bold>Materials and methods:<\/jats:bold> Samples for mutation screening were obtained from patients experiencing resistance to first line TKIs or from patients in acceleration phase (AP) or blast crisis (BC) at the time of diagnosis. The cDNA region corresponding to BCR-ABL1 KD was sequenced by pyrosequencing method. The \u03c7<jats:sup>2<\/jats:sup> test was used to assess the association of categorical variables between mutation-positive and -negative groups. In addition, the Kaplan-Meier method was applied to generate survival curves.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Eight different point mutations were identified in 22 (13.4%) out of 163 CML patients experiencing resistance to TKIs. The types of mutations detected were as follows: Contact binding site mutations 50% (11), SH2 domain mutations 27.4% (six), P-loop mutations 18.1% (four), and SH3 domain mutations accounting for 4.5% (one). The most common mutation was T315I, accounting for 5% (<jats:italic>n<\/jats:italic> = 8) of all patients. Significant association was identified between BCR-ABL1 mutations and additional chromosomal aberrations as well as between the mutations and disease phases (<jats:italic>p<\/jats:italic> &amp;lt; 0.05). Twelve out of 22 patients with BCR-ABL1 mutations and seven out of eight with T315I were in BC. Overall survival (OS) of the patients with BCR-ABL1 mutations was significantly lower comparing to the patients with no mutation (<jats:italic>p<\/jats:italic> &amp;lt; 0.05) and 8 patients with T315I mutation presented OS of 0%.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> T315I was the most commonly identified BCR-ABL1 mutation in TKI-resistant CML patients of Azerbaijani origin, being associated with disease progression and poor OS.<\/jats:p>","DOI":"10.3389\/pore.2023.1611518","type":"journal-article","created":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T04:11:39Z","timestamp":1703218299000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Spectrum of BCR-ABL mutations in Azerbaijanian imatinib-resistant patients with chronic myeloid leukemia"],"prefix":"10.3389","volume":"29","author":[{"given":"Aypara","family":"Hasanova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chingiz","family":"Asadov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigar","family":"Karimova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aytan","family":"Shirinova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunay","family":"Aliyeva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zohra","family":"Alimirzoyeva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,12,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1182\/blood-2013-05-501569","article-title":"European leukemianet recommendations for the management of chronic myeloid leukemia","volume":"122","author":"Baccarani","year":"2013","journal-title":"Blood"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.1016\/S0140-6736(13)62120-0","article-title":"Chronic myeloid leukaemia","volume":"385","author":"Apperley","year":"2015","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1056\/nejmoa022457","article-title":"Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia","volume":"348","author":"O\u2019Brien","year":"2003","journal-title":"N Engl J Med"},{"key":"B4","first-page":"513e21","article-title":"Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia in Europe 2006: transplant activity, long-term data and current results. An analysis by the chronic leukemia working party of the european group for blood and marrow transplantation (EBMT)","volume":"91","author":"Gratwohl","year":"2006","journal-title":"Haematologica"},{"key":"B5","doi-asserted-by":"publisher","first-page":"4204","DOI":"10.1200\/JCO.2009.21.8230","article-title":"Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase","volume":"27","author":"Hughes","year":"2009","journal-title":"J Clin Oncol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"4944","DOI":"10.1182\/blood-2009-04-214221","article-title":"Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations","volume":"114","author":"M\u00fcller","year":"2009","journal-title":"Blood"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1870","DOI":"10.1182\/blood-2015-09-666214","article-title":"The impact of multiple low-level BCR-ABL1 mutations on response to ponatinib","volume":"127","author":"Parker","year":"2016","journal-title":"Blood"},{"key":"B8","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.leukres.2017.01.005","article-title":"Current approach to the treatment of chronic myeloid leukaemia","volume":"55","author":"Pasic","year":"2017","journal-title":"Leuk Res"},{"key":"B9","doi-asserted-by":"publisher","first-page":"939","DOI":"10.3389\/fonc.2019.00939","article-title":"BCR-ABL independent mechanisms of resistance in chronic myeloid leukemia","volume":"9","author":"Loscocco","year":"2019","journal-title":"Front Oncol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1007\/s11899-015-0248-3","article-title":"Chronic myeloid leukemia: advances in understanding disease biology and mechanisms of resistance to tyrosine kinase inhibitors","volume":"10","author":"Eide","year":"2015","journal-title":"Curr Hematol Malig Rep"},{"key":"B11","doi-asserted-by":"publisher","first-page":"x274","DOI":"10.1093\/annonc\/mdl273","article-title":"Chronic myelogenous leukemia (CML): resistance to tyrosine kinase inhibitors","volume":"17","author":"Hochhaus","year":"2006","journal-title":"Ann Oncol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"6041","DOI":"10.1200\/JCO.2009.25.0779","article-title":"Chronicmyeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet","volume":"27","author":"Baccarani","year":"2009","journal-title":"J Clin Oncol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.6004\/jnccn.2013.0157","article-title":"Chronic myelogenous leukemia, version 1.2014","volume":"11","author":"O\u2019Brien","year":"2013","journal-title":"J Natl Compr Canc Netw"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1016\/S1470-2045(07)70342-X","article-title":"Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia","volume":"8","author":"Apperley","year":"2007","journal-title":"Lancet Oncol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1182\/blood-2012-05-431379","article-title":"BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: frequency and clonal relationships","volume":"121","author":"Khorashad","year":"2013","journal-title":"Blood"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1182\/blood-2010-12-326405","article-title":"BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet","volume":"118","author":"Soverini","year":"2011","journal-title":"Blood"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.1182\/blood-2009-01-199307","article-title":"KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR\/ABL translocation","volume":"114","author":"Shiotsu","year":"2009","journal-title":"Blood"},{"key":"B18","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/leu.2010.15","article-title":"Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias","volume":"24","author":"Moore","year":"2010","journal-title":"Leukemia"},{"key":"B19","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1182\/blood-2006-05-025049","article-title":"MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation","volume":"109","author":"Giles","year":"2007","journal-title":"Blood"},{"key":"B20","doi-asserted-by":"publisher","first-page":"7987","DOI":"10.1158\/0008-5472.CAN-07-1825","article-title":"Crystal structure of the T315I Abl mutant in complex with the aurora kinases inhibitor PHA-739358","volume":"67","author":"Modugno","year":"2007","journal-title":"Cancer Res"},{"key":"B21","doi-asserted-by":"publisher","first-page":"4204","DOI":"10.1200\/JCO.2009.21.8230","article-title":"Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase","volume":"27","author":"Hughes","year":"2009","journal-title":"J Clin Oncol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2168","DOI":"10.1182\/blood-2009-01-197186","article-title":"Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors","volume":"114","author":"Soverini","year":"2009","journal-title":"Blood"},{"key":"B23","doi-asserted-by":"publisher","first-page":"4944","DOI":"10.1182\/blood-2009-04-214221","article-title":"Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations","volume":"114","author":"Muller","year":"2009","journal-title":"Blood"},{"key":"B24","doi-asserted-by":"publisher","first-page":"2562","DOI":"10.1172\/JCI30890","article-title":"Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency","volume":"117","author":"Shah","year":"2007","journal-title":"J Clin Invest"},{"key":"B25","doi-asserted-by":"publisher","first-page":"401","DOI":"10.3324\/haematol.10822","article-title":"Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain","volume":"92","author":"Soverini","year":"2007","journal-title":"Haematological"},{"key":"B26","doi-asserted-by":"publisher","first-page":"2234","DOI":"10.1182\/blood-2011-08-375535","article-title":"Poor response to second-line kinase inhibitors in chronic myeloid leukemia patients with multiple low-level mutations, irrespective of their resistance profile","volume":"119","author":"Parker","year":"2012","journal-title":"Blood"},{"key":"B27","doi-asserted-by":"publisher","first-page":"4250","DOI":"10.1200\/JCO.2011.35.0934","article-title":"Sensitive detection of BCR-ABL1 mutations in patients with chronic myeloid leukemia after imatinib resistance is predictive of outcome during subsequent therapy","volume":"29","author":"Parker","year":"2011","journal-title":"J Clin Oncol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.6004\/jnccn.2020.0047","article-title":"Chronic myeloid leukemia, version 2.2021, NCCN clinical practice guidelines in oncology","volume":"18","author":"Deininger","year":"2020","journal-title":"NCCN Clinical Practice Guidelines Oncology"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1016\/S1470-2045(07)70342-X","article-title":"Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia","volume":"8","author":"Apperley","year":"2007","journal-title":"Lancet Oncol"},{"key":"B30","doi-asserted-by":"publisher","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":"B31","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1111\/bjh.13966","article-title":"Present and future of molecular monitoring in chronic myeloid leukaemia","volume":"173","author":"Soverini","year":"2016","journal-title":"Br J Haematol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"4611","DOI":"10.1182\/blood-2002-12-3659","article-title":"Several BCR-ABL kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib","volume":"101","author":"Corbin","year":"2003","journal-title":"Blood"},{"key":"B33","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/j.beha.2009.05.004","article-title":"Cause and management of therapy resistance","volume":"22","author":"Hochhaus","year":"2009","journal-title":"Best Pract Res Clin Haematol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"S120","DOI":"10.1016\/j.clml.2015.02.035","article-title":"Mutations in the BCR-ABL1 kinase domain and elsewhere in chronic myeloid leukemia","author":"Soverini","year":"2015","journal-title":"Clin Lymphoma Myeloma Leuk"},{"key":"B35","doi-asserted-by":"publisher","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"}],"container-title":["Pathology and Oncology Research"],"original-title":[],"link":[{"URL":"https:\/\/www.por-journal.com\/articles\/10.3389\/pore.2023.1611518\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T04:11:42Z","timestamp":1703218302000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.por-journal.com\/articles\/10.3389\/pore.2023.1611518\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,22]]},"references-count":35,"alternative-id":["10.3389\/pore.2023.1611518"],"URL":"https:\/\/doi.org\/10.3389\/pore.2023.1611518","relation":{},"ISSN":["1532-2807"],"issn-type":[{"value":"1532-2807","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,22]]},"article-number":"1611518"}}