{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T09:16:12Z","timestamp":1770282972145,"version":"3.49.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T00:00:00Z","timestamp":1681257600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by a BCR-ABL fusion gene. Imatinib has significantly improved the treatment of CML as a first-generation tyrosine kinase inhibitor (TKIs). The T315I mutant form of BCR-ABL is the most common mutation that confers resistance to imatinib or the second-generation TKIs, resulting in poor clinical prognosis. In this work, we assessed the effect of a potent histone deacetylase (HDAC) inhibitor, I13, on the differentiation blockade in CML cells harboring T315I-mutated and wild-type BCR-ABL by MTT assay, flow cytometery, cell colony formation assay, mRNA Sequencing, Quantitative real-time PCR and Western blotting analysis. We found that I13 possessed highly potent activity against T315I-mutated BCR-ABL mutant-expressing cells and wild-type BCR-ABL-expressing cells. I13 induced cell differentiation and significantly suppressed the proliferation of these CML cells <jats:italic>via<\/jats:italic> the cell cycle G0\/G1-phase accumulation. Moreover, it was revealed that I13 triggered the differentiation of BaF3-T315I cells, which was attributed to the block of the chronic myeloid leukemia signaling pathway <jats:italic>via<\/jats:italic> the depletion of BCR-ABL that was mediated by the inhibition of HDAC activity presented by the acetylation of histones H3 and H4. Taken together, I13 efficiently depleted BCR-ABL in CML cells expressing the BCR-ABL-T315I mutation, which blocked its function, serving as a scaffold protein that modulated the chronic myeloid leukemia signaling pathway mediating cell differentiation. The present findings demonstrate that I13 is a BCR-ABL modulator for the development of CML therapy that can override resistance caused by T315I-mutated BCR-ABL.<\/jats:p>","DOI":"10.3389\/fphar.2023.1183052","type":"journal-article","created":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T05:53:56Z","timestamp":1681278836000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["I13 overrides resistance mediated by the T315I mutation in chronic myeloid leukemia by direct BCR-ABL inhibition"],"prefix":"10.3389","volume":"14","author":[{"given":"Congying","family":"Gao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yun","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangyu","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peilei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhe-Sheng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liuya","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,4,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1016\/j.leukres.2009.08.021","article-title":"Histone deacetylase inhibitors: A new perspective for the treatment of leukemia","volume":"34","author":"Abujamra","year":"2010","journal-title":"Leuk. Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1039\/c5ib00206k","article-title":"Assessment of the potential of a high frequency acoustomicrofluidic nebulisation platform for inhaled stem cell therapy","volume":"8","author":"Alhasan","year":"2016","journal-title":"Integr. Biol. (Camb)."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2147\/BLCTT.S130197","article-title":"Spotlight on ponatinib in the treatment of chronic myeloid leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia: Patient selection and perspectives","volume":"8","author":"Anagnostou","year":"2018","journal-title":"Blood Lymphat. Cancer"},{"key":"B4","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1016\/j.ccell.2020.03.006","article-title":"Response and resistance to BCR-ABL1-targeted therapies","volume":"37","author":"Braun","year":"2020","journal-title":"Cancer Cell"},{"key":"B5","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1196\/annals.1378.038","article-title":"Reduction of Bcr-Abl function leads to erythroid differentiation of K562 cells via downregulation of ERK","volume":"1090","author":"Brozik","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1111\/j.1365-2141.2005.05873.x","article-title":"P210 Bcr-abl tyrosine kinase interaction with histone deacetylase 1 modifies histone H4 acetylation and chromatin structure of chronic myeloid leukaemia haematopoietic progenitors","volume":"132","author":"Brusa","year":"2006","journal-title":"Br. J. Haematol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1080\/14756366.2020.1870457","article-title":"Discovery of indole-3-butyric acid derivatives as potent histone deacetylase inhibitors","volume":"36","author":"Chen","year":"2021","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2075","DOI":"10.1056\/NEJMoa1205127","article-title":"Ponatinib in refractory Philadelphia chromosome-positive leukemias","volume":"367","author":"Cortes","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/s13045-021-01055-9","article-title":"Third-line therapy for chronic myeloid leukemia: Current status and future directions","volume":"14","author":"Cortes","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1914","DOI":"10.1016\/S0140-6736(21)01204-6","article-title":"Chronic myeloid leukaemia","volume":"398","author":"Cortes","year":"2021","journal-title":"Lancet"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1414","DOI":"10.3390\/ijms18071414","article-title":"Histone deacetylase inhibitors as anticancer drugs","volume":"18","author":"Eckschlager","year":"2017","journal-title":"Int. J. Mol. Sci."},{"key":"B12","doi-asserted-by":"publisher","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":"B13","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"},{"key":"B14","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1002\/ajh.25792","article-title":"Chronic myeloid leukemia: 2020 update on diagnosis, therapy and monitoring","volume":"95","author":"Jabbour","year":"2020","journal-title":"Am. J. Hematol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1182\/blood-2007-11-123950","article-title":"Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation following failure of imatinib mesylate therapy","volume":"112","author":"Jabbour","year":"2008","journal-title":"Blood"},{"key":"B16","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1002\/cncr.24066","article-title":"Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase","volume":"115","author":"Kantarjian","year":"2009","journal-title":"Cancer"},{"key":"B17","doi-asserted-by":"publisher","first-page":"e2913","DOI":"10.1038\/cddis.2017.284","article-title":"Platinum pyrithione induces apoptosis in chronic myeloid leukemia cells resistant to imatinib via DUB inhibition-dependent caspase activation and Bcr-Abl downregulation","volume":"8","author":"Lan","year":"2017","journal-title":"Cell Death Dis."},{"key":"B18","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1007\/s12185-021-03126-6","article-title":"Target spectrum of the BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia","volume":"113","author":"Lee","year":"2021","journal-title":"Int. J. Hematol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1522","DOI":"10.1158\/0008-5472.CAN-17-1733","article-title":"Antitumor effects of blocking protein neddylation in T315I-BCR-ABL leukemia cells and leukemia stem cells","volume":"78","author":"Liu","year":"2018","journal-title":"Cancer Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"855570","DOI":"10.3389\/fonc.2022.855570","article-title":"The histone deacetylase inhibitor I13 induces differentiation of M2, M3 and M5 subtypes of acute myeloid leukemia cells and leukemic stem-like cells","volume":"12","author":"Ma","year":"2022","journal-title":"Front. Oncol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.bioorg.2016.05.005","article-title":"Inhibitors of histone deacetylase as antitumor agents: A critical review","volume":"67","author":"Manal","year":"2016","journal-title":"Bioorg Chem."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1093\/jnci\/92.15.1210","article-title":"Histone deacetylase inhibitors: Inducers of differentiation or apoptosis of transformed cells","volume":"92","author":"Marks","year":"2000","journal-title":"J. Natl. Cancer Inst."},{"key":"B23","doi-asserted-by":"publisher","first-page":"117","DOI":"10.3390\/cells10010117","article-title":"Chronic myeloid leukemia: A model disease of the past, present and future","volume":"10","author":"Minciacchi","year":"2021","journal-title":"Cells"},{"key":"B24","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1248\/bpb.b15-00103","article-title":"Therapeutic drug monitoring of imatinib, nilotinib, and dasatinib for patients with chronic myeloid leukemia","volume":"38","author":"Miura","year":"2015","journal-title":"Biol. Pharm. Bull."},{"key":"B25","doi-asserted-by":"publisher","first-page":"313","DOI":"10.3233\/BIO-2009-1085","article-title":"Radicicol-mediated inhibition of Bcr-Abl in K562 cells induced p38-MAPK dependent erythroid differentiation and PU.1 down-regulation","volume":"34","author":"Morceau","year":"2008","journal-title":"Biofactors"},{"key":"B26","doi-asserted-by":"publisher","first-page":"4210","DOI":"10.1200\/JCO.2015.62.4718","article-title":"Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia","volume":"33","author":"Moslehi","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.1038\/sj.leu.2404733","article-title":"Chronic myeloid leukemia--some topical issues","volume":"21","author":"Mughal","year":"2007","journal-title":"Leukemia"},{"key":"B28","first-page":"5126","article-title":"Histone deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylate-sensitive or -refractory chronic myelogenous leukemia-blast crisis cells","volume":"63","author":"Nimmanapalli","year":"2003","journal-title":"Cancer Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"3236","DOI":"10.1182\/blood-2002-08-2675","article-title":"Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells","volume":"101","author":"Nimmanapalli","year":"2003","journal-title":"Blood"},{"key":"B30","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1038\/nrc3317","article-title":"Pushing the limits of targeted therapy in chronic myeloid leukaemia","volume":"12","author":"O'Hare","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"B31","doi-asserted-by":"publisher","first-page":"100825","DOI":"10.1016\/j.blre.2021.100825","article-title":"Chronic Myeloid Leukemia: Modern therapies, current challenges and future directions","volume":"49","author":"Osman","year":"2021","journal-title":"Blood Rev."},{"key":"B32","doi-asserted-by":"publisher","first-page":"106337","DOI":"10.1016\/j.leukres.2020.106337","article-title":"Novel therapeutic approaches in chronic myeloid leukemia","volume":"91","author":"Ozgur Yurttas","year":"2020","journal-title":"Leuk. Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.2174\/0929867327666200203113926","article-title":"Romidepsin (FK228), A histone deacetylase inhibitor and its analogues in cancer chemotherapy","volume":"28","author":"Pojani","year":"2021","journal-title":"Curr. Med. Chem."},{"key":"B34","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/sj.leu.2403999","article-title":"Transient or long-term silencing of BCR-ABL alone induces cell cycle and proliferation arrest, apoptosis and differentiation","volume":"20","author":"Rangatia","year":"2006","journal-title":"Leukemia"},{"key":"B35","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1634\/theoncologist.2009-0297","article-title":"Why doesn't imatinib cure chronic myeloid leukemia?","volume":"15","author":"Redner","year":"2010","journal-title":"Oncologist"},{"key":"B36","doi-asserted-by":"publisher","first-page":"112171","DOI":"10.1016\/j.ejmech.2020.112171","article-title":"Histone deacetylase 3 (HDAC3) inhibitors as anticancer agents: A review","volume":"192","author":"Sarkar","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"B37","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1159\/000501927","article-title":"Ponatinib in the treatment of chronic myeloid leukemia and philadelphia chromosome-positive acute leukemia: Recommendations of a German expert consensus panel with focus on cardiovascular management","volume":"143","author":"Saussele","year":"2020","journal-title":"Acta Haematol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1007\/s13238-020-00694-x","article-title":"HDAC inhibitors overcome immunotherapy resistance in B-cell lymphoma","volume":"11","author":"Wang","year":"2020","journal-title":"Protein Cell"},{"key":"B39","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.omto.2020.06.008","article-title":"A small molecule inhibitor, OGP46, is effective against imatinib-resistant BCR-ABL mutations via the BCR-ABL\/JAK-STAT pathway","volume":"18","author":"Wei","year":"2020","journal-title":"Mol. Ther. Oncolytics"},{"key":"B40","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1007\/s11899-018-0474-6","article-title":"Chronic myeloid leukemia: Beyond BCR-ABL1","volume":"13","author":"Zhou","year":"2018","journal-title":"Curr. Hematol. Malig. Rep."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1183052\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T05:53:59Z","timestamp":1681278839000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1183052\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,12]]},"references-count":40,"alternative-id":["10.3389\/fphar.2023.1183052"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2023.1183052","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,12]]},"article-number":"1183052"}}