oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2025-24-4-66-81oncotomsk-3766Research ArticleЛАБОРАТОРНЫЕ И ЭКСПЕРИМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯLABORATORY AND EXPERIMENTAL STUDIESКластер miR-17-92 и miR-203А как предикторы течения хронического миелолейкозаmiR-17-92 and miR-203A clusters as predictors of the clinical course of chronic myeloid leukemiahttps://orcid.org/0000-0001-5791-3714ПерепечаеваМ. Л.PerepechaevaM. L.

Перепечаева Мария Леонидовна, кандидат биологических наук, старший научный сотрудник, Научно-исследовательский институт молекулярной биологии и биофизики Researcher ID (WOS): AAG-1840-2020. Author ID (Scopus): 8283410900. 

630060, г. Новосибирск, ул. Тимакова, 2

Maria L. Perepechaeva, PhD, Senior Researcher, Institute of Molecular Biology and Biophysics Researcher ID (WOS): AAG-1840-2020. Author ID (Scopus): 8283410900.

2/12, Timakova St., Novosibirsk, 630117

mlperepechaeva@frcftm.ruhttps://orcid.org/0000-0002-8129-9176ГореваО. Б.GorevaO. B.

Горева Ольга Борисовна, кандидат биологических наук, старший научный сотрудник, Научно-исследовательский институт молекулярной биологии и биофизики Researcher ID (WOS): K-3428-2013. Author ID (Scopus): 8691755700.

630060, г. Новосибирск, ул. Тимакова, 2

Olga B. Goreva, PhD, Senior Researcher, Institute of Molecular Biology and Biophysics Researcher ID (WOS): K-3428-2013. Author ID (Scopus): 8691755700.

2/12, Timakova St., Novosibirsk, 630117

https://orcid.org/0000-0002-2516-0778ЛямкинаА. С.LyamkinaA. S.

Лямкина Анна Сергеевна, кандидат медицинских наук, доцент кафедры терапии, гематологии и трансфузиологии ФПК и ППВ Researcher ID (WOS): Y-7192-2018. Author ID (Scopus): 16310262000.

630091, г. Новосибирск, Красный пр-т, 52

Anna S. Lyamkina, MD, PhD, Associate Professor of the Department of Therapy, Hematology and Transfusiology, Faculty of Advanced Training and Practical Veterinary Medicine Researcher ID (WOS): Y-7192-2018. Author ID (Scopus): 16310262000.

52, Krasny Prospect, Novosibirsk, 630091

https://orcid.org/0000-0001-6791-0314ПоспеловаТ. И.PospelovaT. I.

Поспелова Татьяна Ивановна, доктор медицинских наук, профессор, заведующая кафедрой терапии, гематологии и трансфузиологии ФПК и ППВ Author ID (Scopus): 7005792562. 

630091, г. Новосибирск, Красный пр-т, 52

Tatyana I. Pospelova, MD, PhD, Professor, Head of the Department of Therapy, Hematology and Transfusiology, Faculty of Advanced Training and Practical Veterinary Medicine Author ID (Scopus): 7005792562.

52, Krasny Prospect, Novosibirsk, 630091

https://orcid.org/0000-0002-5894-1159ГришановаА. Ю.GrishanovaA. Yu.

Гришанова Алевтина Юрьевна, доктор биологических наук, профессор, главный научный сотрудник, заведующая лабораторией чужеродных соединений, Научно-исследовательский институт молекулярной биологии и биофизики Researcher ID (WOS): C-1759-2014. Author ID (Scopus): 7004298657.

630060, г. Новосибирск, ул. Тимакова, 2

Alevtina Yu. Grishanova, DSc, Professor, Chief Researcher, Head of the Laboratory of Foreign Compounds, Institute of Molecular Biology and Biophysics Researcher ID (WOS): C-1759-2014. Author ID (Scopus): 7004298657.

2/12, Timakova St., Novosibirsk, 630117

Научно-исследовательский институт молекулярной биологии и биофизики ФГБНУ «Федеральный исследовательский центр фундаментальной и трансляционной медицины»РоссияInstitute of Molecular Biology and Biophysics, Federal Research Center for Fundamental and translational MedicineRussian FederationФГБОУ ВО «Новосибирский государственный медицинский университет» Минздрава РоссииРоссияNovosibirsk State Medical University, Ministry of Health of RussiaRussian Federation2025011020252446681Copyright © Перепечаева М.Л., Горева О.Б., Лямкина А.С., Поспелова Т.И., Гришанова А.Ю., 20252025Перепечаева М.Л., Горева О.Б., Лямкина А.С., Поспелова Т.И., Гришанова А.Ю.Perepechaeva M.L., Goreva O.B., Lyamkina A.S., Pospelova T.I., Grishanova A.Y.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/3766

Введение. В терапии хронического миелолейкоза (ХМЛ) в настоящее время повсеместно применяются ингибиторы тирозинкиназ, и прогрессирование заболевания часто связано с развитием резистентности к ним. Существует потребность в дополнительных инструментах контроля терапии, и таковыми могут стать уровни экспрессии определенных микроРНК (miR). Цель исследования – оценка уровня экспрессии miR-203а и miR-17-92 в костном мозге и субстратах периферической крови – лимфоцитах, плазме и внеклеточных везикулах у пациентов с ХМЛ с разными характеристиками патологического процесса и врачебного вмешательства. Материал и методы. Образцы крови и костного мозга 56 пациентов с диагнозом ХМЛ были взяты из Городского гематологического центра Государственного бюджетного учреждения здравоохранения Новосибирской области «Городская клиническая больница № 2» с 2016 по 2017 гг. Уровень экспрессии miR оценивали методом ОТ-ПЦР в реальном времени по принципу taqMan. Результаты. В костном мозге и лимфоцитах крови уровень экспрессии miR-17, miR-18а и miR-20a оказался выше у пациентов в фазе акселерации (ФА) по сравнению с хронической фазой (ХФ), а также у больных с неблагоприятным прогнозом. Уровень экспрессии miR-19a и miR-19b в плазме был выше у пациентов с ХФ по сравнению с бластным кризом (БК) и у пациентов с благоприятным прогнозом. Уровень экспрессии miR-19а был выше у пациентов с благоприятным прогнозом в микровезикулах, а уровень экспрессии miR-203 был выше у пациентов с благоприятным прогнозом в микровезикулах и плазме крови. Также экспрессия miR-203 оказалась существенно выше в микровезикулах у пациентов, достигших большого молекулярного ответа (БМО). Заключение. Наиболее перспективными в плане возможного практического применения представляются miR-17, miR-18а и miR-20a в костном мозге и лимфоцитах, miR-19a и miR-19b в плазме крови, а также miR-203 в плазме крови и в микровезикулах.

Background. Tyrosine kinase inhibitors are now widely used for the treatment of chronic myeloid leukemia (CML), and disease progression is often linked with the development of resistance to these drugs. There is a need for additional theranostic tools, and they may include expression levels of certain microRNAs (miR). Purpose: to study expression levels of miR-203a and of miR-17-92 cluster members in bone marrow and peripheral-blood components (lymphocytes, plasma, and extracellular vesicles) from CML patients with various clinical characteristics and treatment responses. Material and Methods. Blood and bone marrow samples were collected from 56 patients having a CML diagnosis from the City Hematology Center at the government-funded healthcare institution (Novosibirsk Oblast) City Clinical Hospital No. 2 from the years 2016 to 2017. Expression levels of miRNAs were quantifed by reverse-transcription real-time PCR according to the TaqMan principle. Results. In bone marrow and blood lymphocytes, expression levels of miR-17, miR-18а, and miR-20a were higher in patients in the acceleration phase (FA) as compared to the chronic phase (CF) and in patients with an unfavorable prognosis. In plasma, expression levels of miR-19a and miR-19b were higher in patients with CF compared to the blast crisis (BC) phase and higher in patients with a favorable prognosis. MiR-19a expression was also higher in extracellular vesicles of patients with a favorable prognosis, and miR-203 expression was higher in patients with a favorable prognosis in extracellular vesicles and in blood plasma. Furthermore, miR-203 expression proved to be signifcantly greater in extracellular vesicles of patients who achieved a major molecular response. Conclusion. MiR-17, miR-18а, and miR-20a in bone marrow and lymphocytes seem to be the most promising for the possible practical application, and the same is true for miR-19a and miR-19b in blood plasma and miR-203 in blood plasma and extracellular vesicles.

ХМЛmiR-203аmiR-17-92внеклеточные везикулылимфоцитыпериферическая кровькостный мозгфазы ХМЛпрогноз ХМЛCMLmiR-203àmiR-17-92extracellular vesicleslymphocytesperipheral bloodbone marrowCML phaseCML prognosisРабота выполнена в рамках государственного задания Министерства науки и высшего образования Российской Федерации (тема № 125031203556-7, код FGMU-2025-0004) с использованием оборудования ЦКП «Протеомный анализ».The research was carried out within the state assignment of Ministry of Science and Higher Education of the Russian Federation (theme No. 125031203556-7, FGMU-2025-0004) using the equipment of the Core Facility “Proteomic Analysis”.ReferencesMinciacchi V.R., Kumar R., Krause D.S. Chronic Myeloid Leukemia: A Model Disease of the Past, Present and Future. Cells. 2021; 10(1): 117. doi: 10.3390/cells10010117.Minciacchi V.R., Kumar R., Krause D.S. Chronic Myeloid Leukemia: A Model Disease of the Past, Present and Future. Cells. 2021; 10(1): 117. doi: 10.3390/cells10010117.Hochhaus A., Baccarani M., Silver R.T., Schiffer C., Apperley J.F., Cervantes F., Clark R.E., Cortes J.E., Deininger M.W., Guilhot F., HjorthHansen H., Hughes T.P., Janssen J., Kantarjian H.M., Kim D.W., Larson R.A., Lipton J.H., Mahon F.X., Mayer J., Nicolini F., Niederwieser D., Pane F., Radich J.P., Rea D., Richter J., Rosti G., Rousselot P., Saglio G., Saussele S., Soverini S., Steegmann J.L., Turkina A., Zaritskey A., Hehlmann R. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020; 34(4): 966–84. doi: 10.1038/s41375-020-0776-2.Hochhaus A., Baccarani M., Silver R.T., Schiffer C., Apperley J.F., Cervantes F., Clark R.E., Cortes J.E., Deininger M.W., Guilhot F., HjorthHansen H., Hughes T.P., Janssen J., Kantarjian H.M., Kim D.W., Larson R.A., Lipton J.H., Mahon F.X., Mayer J., Nicolini F., Niederwieser D., Pane F., Radich J.P., Rea D., Richter J., Rosti G., Rousselot P., Saglio G., Saussele S., Soverini S., Steegmann J.L., Turkina A., Zaritskey A., Hehlmann R. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020; 34(4): 966–84. doi: 10.1038/s41375-020-0776-2.Cross N.C.P., Ernst T., Branford S., Cayuela J.M., Deininger M., Fabarius A., Kim D.D.H., Machova Polakova K., Radich J.P., Hehlmann R., Hochhaus A., Apperley J.F., Soverini S. European LeukemiaNet laboratory recommendations for the diagnosis and management of chronic myeloid leukemia. Leukemia. 2023; 37(11): 2150–67. doi: 10.1038/s41375-023-02048-y.Cross N.C.P., Ernst T., Branford S., Cayuela J.M., Deininger M., Fabarius A., Kim D.D.H., Machova Polakova K., Radich J.P., Hehlmann R., Hochhaus A., Apperley J.F., Soverini S. European LeukemiaNet laboratory recommendations for the diagnosis and management of chronic myeloid leukemia. Leukemia. 2023; 37(11): 2150–67. doi: 10.1038/s41375-023-02048-y.Khoury J.D., Solary E., Abla O., Akkari Y., Alaggio R., Apperley J.F., Bejar R., Berti E., Busque L., Chan J.K.C., Chen W., Chen X., Chng W.J., Choi J.K., Colmenero I., Coupland S.E., Cross N.C.P., De Jong D., Elghetany M.T., Takahashi E., Emile J.F., Ferry J., Fogelstrand L., Fontenay M., Germing U., Gujral S., Haferlach T., Harrison C., Hodge J.C., Hu S., Jansen J.H., Kanagal-Shamanna R., Kantarjian H.M., Kratz C.P., Li X.Q., Lim M.S., Loeb K., Loghavi S., Marcogliese A., Meshinchi S., Michaels P., Naresh K.N., Natkunam Y., Nejati R., Ott G., Padron E., Patel K.P., Patkar N., Picarsic J., Platzbecker U., Roberts I., Schuh A., Sewell W., Siebert R., Tembhare P., Tyner J., Verstovsek S., Wang W., Wood B., Xiao W., Yeung C., Hochhaus A. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022; 36(7): 1703–19. doi: 10.1038/s41375-022-01613-1.Khoury J.D., Solary E., Abla O., Akkari Y., Alaggio R., Apperley J.F., Bejar R., Berti E., Busque L., Chan J.K.C., Chen W., Chen X., Chng W.J., Choi J.K., Colmenero I., Coupland S.E., Cross N.C.P., De Jong D., Elghetany M.T., Takahashi E., Emile J.F., Ferry J., Fogelstrand L., Fontenay M., Germing U., Gujral S., Haferlach T., Harrison C., Hodge J.C., Hu S., Jansen J.H., Kanagal-Shamanna R., Kantarjian H.M., Kratz C.P., Li X.Q., Lim M.S., Loeb K., Loghavi S., Marcogliese A., Meshinchi S., Michaels P., Naresh K.N., Natkunam Y., Nejati R., Ott G., Padron E., Patel K.P., Patkar N., Picarsic J., Platzbecker U., Roberts I., Schuh A., Sewell W., Siebert R., Tembhare P., Tyner J., Verstovsek S., Wang W., Wood B., Xiao W., Yeung C., Hochhaus A. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022; 36(7): 1703–19. doi: 10.1038/s41375-022-01613-1.Hussein B.M., Hidayat H.J., Salihi A., Sabir D.K., Taheri M., Ghafouri-Fard S. MicroRNA: A signature for cancer progression. Biomed Pharmacother. 2021; 138: 111528. doi: 10.1016/j.biopha.2021.111528.Hussein B.M., Hidayat H.J., Salihi A., Sabir D.K., Taheri M., Ghafouri-Fard S. MicroRNA: A signature for cancer progression. Biomed Pharmacother. 2021; 138: 111528. doi: 10.1016/j.biopha.2021.111528.Condrat C.E., Thompson D.C., Barbu M.G., Bugnar O.L., Boboc A., Cretoiu D., Suciu N., Cretoiu S.M., Voinea S.C. miRNAs as Biomarkers in Disease: Latest Findings Regarding Their Role in Diagnosis and Prognosis. Cells. 2020; 9(2): 276. doi: 10.3390/cells9020276.Condrat C.E., Thompson D.C., Barbu M.G., Bugnar O.L., Boboc A., Cretoiu D., Suciu N., Cretoiu S.M., Voinea S.C. miRNAs as Biomarkers in Disease: Latest Findings Regarding Their Role in Diagnosis and Prognosis. Cells. 2020; 9(2): 276. doi: 10.3390/cells9020276.Miura N., Hasegawa J., Shiota G. Serum messenger RNA as a biomarker and its clinical usefulness in malignancies. Clin Med Oncol. 2008; 2: 511–27. doi: 10.4137/cmo.s379.Miura N., Hasegawa J., Shiota G. Serum messenger RNA as a biomarker and its clinical usefulness in malignancies. Clin Med Oncol. 2008; 2: 511–27. doi: 10.4137/cmo.s379.Bai X., Hua S., Zhang J., Xu S. The MicroRNA Family Both in Normal Development and in Different Diseases: The miR-17-92 Cluster. Biomed Res Int. 2019: 9450240. doi: 10.1155/2019/9450240.Bai X., Hua S., Zhang J., Xu S. The MicroRNA Family Both in Normal Development and in Different Diseases: The miR-17-92 Cluster. Biomed Res Int. 2019: 9450240. doi: 10.1155/2019/9450240.Khuu C., Utheim T.P., Sehic A. The Three Paralogous MicroRNA Clusters in Development and Disease, miR-17-92, miR-106- a-363, and miR-106b-25. Scientifica (Cairo). 2016: 1379643. doi: 10.1155/2016/1379643.Khuu C., Utheim T.P., Sehic A. The Three Paralogous MicroRNA Clusters in Development and Disease, miR-17-92, miR-106- a-363, and miR-106b-25. Scientifica (Cairo). 2016: 1379643. doi: 10.1155/2016/1379643.Bonauer A., Dimmeler S. The microRNA-17-92 cluster: still a miRacle? Cell Cycle. 2009; 8(23): 3866–73. doi: 10.4161/cc.8.23.9994.Bonauer A., Dimmeler S. The microRNA-17-92 cluster: still a miRacle? Cell Cycle. 2009; 8(23): 3866–73. doi: 10.4161/cc.8.23.9994.Li M., Guan X., Sun Y., Mi J., Shu X., Liu F., Li C. miR-92a family and their target genes in tumorigenesis and metastasis. Exp Cell Res. 2014; 323(1): 1–6. doi: 10.1016/j.yexcr.2013.12.025.Li M., Guan X., Sun Y., Mi J., Shu X., Liu F., Li C. miR-92a family and their target genes in tumorigenesis and metastasis. Exp Cell Res. 2014; 323(1): 1–6. doi: 10.1016/j.yexcr.2013.12.025.Venturini L., Battmer K., Castoldi M., Schultheis B., Hochhaus A., Muckenthaler M.U., Ganser A., Eder M., Scherr M. Expression of the miR- 17-92 polycistron in chronic myeloid leukemia (CML) CD34+ cells. Blood. 2007; 109(10): 4399–405. doi: 10.1182/blood-2006-09-045104.Venturini L., Battmer K., Castoldi M., Schultheis B., Hochhaus A., Muckenthaler M.U., Ganser A., Eder M., Scherr M. Expression of the miR- 17-92 polycistron in chronic myeloid leukemia (CML) CD34+ cells. Blood. 2007; 109(10): 4399–405. doi: 10.1182/blood-2006-09-045104.Zhao W., Gupta A., Krawczyk J., Gupta S. The miR-17-92 cluster: Yin and Yang in human cancers. Cancer Treat Res Commun. 2022; 33: 100647. doi: 10.1016/j.ctarc.2022.100647.Zhao W., Gupta A., Krawczyk J., Gupta S. The miR-17-92 cluster: Yin and Yang in human cancers. Cancer Treat Res Commun. 2022; 33: 100647. doi: 10.1016/j.ctarc.2022.100647.Jimbu L., Mesaros O., Joldes C., Neaga A., Zaharie L., Zdrenghea M. MicroRNAs Associated with a Bad Prognosis in Acute Myeloid Leukemia and Their Impact on Macrophage Polarization. Biomedicines. 2024; 12(1): 121. doi: 10.3390/biomedicines12010121.Jimbu L., Mesaros O., Joldes C., Neaga A., Zaharie L., Zdrenghea M. MicroRNAs Associated with a Bad Prognosis in Acute Myeloid Leukemia and Their Impact on Macrophage Polarization. Biomedicines. 2024; 12(1): 121. doi: 10.3390/biomedicines12010121.Hu T., Chong Y., Qin H., Kitamura E., Chang C.S., Silva J., Ren M., Cowell J.K. The miR-17/92 cluster is involved in the molecular etiology of the SCLL syndrome driven by the BCR-FGFR1 chimeric kinase. Oncogene. 2018; 37(14): 1926–38. doi: 10.1038/s41388-017-0091-1.Hu T., Chong Y., Qin H., Kitamura E., Chang C.S., Silva J., Ren M., Cowell J.K. The miR-17/92 cluster is involved in the molecular etiology of the SCLL syndrome driven by the BCR-FGFR1 chimeric kinase. Oncogene. 2018; 37(14): 1926–38. doi: 10.1038/s41388-017-0091-1.Huang X., Chen Z., Ni F., Ye X., Qian W. Shikonin overcomes drug resistance and induces necroptosis by regulating the miR-92a-1-5p/MLKL axis in chronic myeloid leukemia. Aging (Albany NY). 2020; 12(17): 17662–80. doi: 10.18632/aging.103844.Huang X., Chen Z., Ni F., Ye X., Qian W. Shikonin overcomes drug resistance and induces necroptosis by regulating the miR-92a-1-5p/MLKL axis in chronic myeloid leukemia. Aging (Albany NY). 2020; 12(17): 17662–80. doi: 10.18632/aging.103844.Jia Q., Sun H., Xiao F., Sai Y., Li Q., Zhang X., Yang S., Wang H., Wang H., Yang Y., Wu C.T., Wang L. miR-17-92 promotes leukemogenesis in chronic myeloid leukemia via targeting A20 and activation of NF-kappaB signaling. Biochem Biophys Res Commun. 2017; 487(4): 868–74. doi: 10.1016/j.bbrc.2017.04.144.Jia Q., Sun H., Xiao F., Sai Y., Li Q., Zhang X., Yang S., Wang H., Wang H., Yang Y., Wu C.T., Wang L. miR-17-92 promotes leukemogenesis in chronic myeloid leukemia via targeting A20 and activation of NF-kappaB signaling. Biochem Biophys Res Commun. 2017; 487(4): 868–74. doi: 10.1016/j.bbrc.2017.04.144.Sawyers C.L., Callahan W., Witte O.N. Dominant negative MYC blocks transformation by ABL oncogenes. Cell. 1992; 70(6): 901–10. doi: 10.1016/0092-8674(92)90241-4.Sawyers C.L., Callahan W., Witte O.N. Dominant negative MYC blocks transformation by ABL oncogenes. Cell. 1992; 70(6): 901–10. doi: 10.1016/0092-8674(92)90241-4.Gasparini C., Celeghini C., Monasta L., Zauli G. NF-kappaB pathways in hematological malignancies. Cell Mol Life Sci. 2014; 71(11): 2083–2102. doi: 10.1007/s00018-013-1545-4.Gasparini C., Celeghini C., Monasta L., Zauli G. NF-kappaB pathways in hematological malignancies. Cell Mol Life Sci. 2014; 71(11): 2083–2102. doi: 10.1007/s00018-013-1545-4.Li S., Li L., Li J., Liang X., Song C., Zou Y. miR-203, fine-tunning neuroinflammation by juggling different components of NF-kappaB signaling. J Neuroinflammation. 2022; 19(1): 84. doi: 10.1186/s12974-022-02451-9.Li S., Li L., Li J., Liang X., Song C., Zou Y. miR-203, fine-tunning neuroinflammation by juggling different components of NF-kappaB signaling. J Neuroinflammation. 2022; 19(1): 84. doi: 10.1186/s12974-022-02451-9.Liu X., Cheng F., Bai X., Zhao T., Zhao L., Wang L., Li M., Wu X., Chen X., Tang P., Wang M., Jiang L., Yan C., Pei F., Gao X., Ma N., Yang B., Zhang Y. MiR-203 is an anti-obese microRNA by targeting apical sodiumdependent bile acid transporter. iScience. 2022; 25(8): 104708. doi: 10.1016/j.isci.2022.104708.Liu X., Cheng F., Bai X., Zhao T., Zhao L., Wang L., Li M., Wu X., Chen X., Tang P., Wang M., Jiang L., Yan C., Pei F., Gao X., Ma N., Yang B., Zhang Y. MiR-203 is an anti-obese microRNA by targeting apical sodiumdependent bile acid transporter. iScience. 2022; 25(8): 104708. doi: 10.1016/j.isci.2022.104708.Liu Z., Huang Y., Han Z., Shen Z., Yu S., Wang T., Dong Z., Kang M. Exosome-mediated miR-25/miR-203 as a potential biomarker for esophageal squamous cell carcinoma: improving early diagnosis and revealing malignancy. Transl Cancer Res. 2021; 10(12): 5174–82. doi: 10.21037/tcr-21-1123.Liu Z., Huang Y., Han Z., Shen Z., Yu S., Wang T., Dong Z., Kang M. Exosome-mediated miR-25/miR-203 as a potential biomarker for esophageal squamous cell carcinoma: improving early diagnosis and revealing malignancy. Transl Cancer Res. 2021; 10(12): 5174–82. doi: 10.21037/tcr-21-1123.Xu M., Gu M., Zhang K., Zhou J., Wang Z., Da J. miR-203 inhibition of renal cancer cell proliferation, migration and invasion by targeting of FGF2. Diagn Pathol. 2015; 10: 24. doi: 10.1186/s13000-015-0255-7.Xu M., Gu M., Zhang K., Zhou J., Wang Z., Da J. miR-203 inhibition of renal cancer cell proliferation, migration and invasion by targeting of FGF2. Diagn Pathol. 2015; 10: 24. doi: 10.1186/s13000-015-0255-7.Han N., Li H., Wang H. MicroRNA-203 inhibits epithelialmesenchymal transition, migration, and invasion of renal cell carcinoma cells via the inactivation of the PI3K/AKT signaling pathway by inhibiting CAV1. Cell Adh Migr. 2020; 14(1): 227–41. doi: 10.1080/19336918.2020.1827665.Han N., Li H., Wang H. MicroRNA-203 inhibits epithelialmesenchymal transition, migration, and invasion of renal cell carcinoma cells via the inactivation of the PI3K/AKT signaling pathway by inhibiting CAV1. Cell Adh Migr. 2020; 14(1): 227–41. doi: 10.1080/19336918.2020.1827665.Shibuta T., Honda E., Shiotsu H., Tanaka Y., Vellasamy S., Shiratsuchi M., Umemura T. Imatinib induces demethylation of miR-203 gene: an epigenetic mechanism of anti-tumor effect of imatinib. Leuk Res. 2013; 37(10): 1278–86. doi: 10.1016/j.leukres.2013.07.019.Shibuta T., Honda E., Shiotsu H., Tanaka Y., Vellasamy S., Shiratsuchi M., Umemura T. Imatinib induces demethylation of miR-203 gene: an epigenetic mechanism of anti-tumor effect of imatinib. Leuk Res. 2013; 37(10): 1278–86. doi: 10.1016/j.leukres.2013.07.019.He J.H., Li Y.M., Li Y.G., Xie X.Y., Wang L., Chun S.Y., Cheng W.J. hsa-miR-203 enhances the sensitivity of leukemia cells to arsenic trioxide. Exp Ther Med. 2013; 5(5): 1315–21. doi: 10.3892/etm.2013.981.He J.H., Li Y.M., Li Y.G., Xie X.Y., Wang L., Chun S.Y., Cheng W.J. hsa-miR-203 enhances the sensitivity of leukemia cells to arsenic trioxide. Exp Ther Med. 2013; 5(5): 1315–21. doi: 10.3892/etm.2013.981.He J., Han Z., An Z., Li Y., Xie X., Zhou J., He S., Lv Y., He M., Qu H., Liu G., Li Y. The miR-203a Regulatory Network Affects the Proliferation of Chronic Myeloid Leukemia K562 Cells. Front Cell Dev Biol. 2021; 9: 616711. doi: 10.3389/fcell.2021.616711.He J., Han Z., An Z., Li Y., Xie X., Zhou J., He S., Lv Y., He M., Qu H., Liu G., Li Y. The miR-203a Regulatory Network Affects the Proliferation of Chronic Myeloid Leukemia K562 Cells. Front Cell Dev Biol. 2021; 9: 616711. doi: 10.3389/fcell.2021.616711.Abdulmawjood B., Costa B., Roma-Rodrigues C., Baptista P.V., Fernandes A.R. Genetic Biomarkers in Chronic Myeloid Leukemia: What Have We Learned So Far? Int J Mol Sci. 2021; 22(22): 12516. doi: 10.3390/ijms222212516.Abdulmawjood B., Costa B., Roma-Rodrigues C., Baptista P.V., Fernandes A.R. Genetic Biomarkers in Chronic Myeloid Leukemia: What Have We Learned So Far? Int J Mol Sci. 2021; 22(22): 12516. doi: 10.3390/ijms222212516.Li Y., Yuan Y., Tao K., Wang X., Xiao Q., Huang Z., Zhong L., Cao W., Wen J., Feng W. Inhibition of BCR/ABL protein expression by miR-203 sensitizes for imatinib mesylate. PLoS One. 2013; 8(4): e61858. doi: 10.1371/journal.pone.0061858.Li Y., Yuan Y., Tao K., Wang X., Xiao Q., Huang Z., Zhong L., Cao W., Wen J., Feng W. Inhibition of BCR/ABL protein expression by miR-203 sensitizes for imatinib mesylate. PLoS One. 2013; 8(4): e61858. doi: 10.1371/journal.pone.0061858.Hallek M., Cheson B.D., Catovsky D., Caligaris-Cappio F., Dighiero G., Dohner H., Hillmen P., Keating M.J., Montserrat E., Rai K.R., Kipps T.J., International Workshop on Chronic Lymphocytic L. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008; 111(12): 5446–56. doi: 10.1182/blood-2007-06-093906.Hallek M., Cheson B.D., Catovsky D., Caligaris-Cappio F., Dighiero G., Dohner H., Hillmen P., Keating M.J., Montserrat E., Rai K.R., Kipps T.J., International Workshop on Chronic Lymphocytic L. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008; 111(12): 5446–56. doi: 10.1182/blood-2007-06-093906.Baccarani M., Deininger M.W., Rosti G., Hochhaus A., Soverini S., Apperley J.F., Cervantes F., Clark R.E., Cortes J.E., Guilhot F., Hjorth-Hansen H., Hughes T.P., Kantarjian H.M., Kim D.W., Larson R.A., Lipton J.H., Mahon F.X., Martinelli G., Mayer J., Muller M.C., Niederwieser D., Pane F., Radich J.P., Rousselot P., Saglio G., Saussele S., Schiffer C., Silver R., Simonsson B., Steegmann J.L., Goldman J.M., Hehlmann R. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013; 122(6): 872–84. doi: 10.1182/blood-2013-05-501569.Baccarani M., Deininger M.W., Rosti G., Hochhaus A., Soverini S., Apperley J.F., Cervantes F., Clark R.E., Cortes J.E., Guilhot F., Hjorth-Hansen H., Hughes T.P., Kantarjian H.M., Kim D.W., Larson R.A., Lipton J.H., Mahon F.X., Martinelli G., Mayer J., Muller M.C., Niederwieser D., Pane F., Radich J.P., Rousselot P., Saglio G., Saussele S., Schiffer C., Silver R., Simonsson B., Steegmann J.L., Goldman J.M., Hehlmann R. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013; 122(6): 872–84. doi: 10.1182/blood-2013-05-501569.Российские клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. Под ред. И.В. Поддубной, В.Г. Савченко. М., 2016. URL: chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://irbis.rmapo.ru/UploadsFilesForIrbis/1f77dc9fc2f08fe5594aa6dee5793a59.pdf.Russian clinical recommendations on diagnostic and treatment of lymphoproliferative disorders. Ed. by I.V. Poddubnaya, V.G. Savchenko. Moscow, 2016. (in Russian). [Internet]. [cited 01.02.2025]. URL: chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://irbis.rmapo.ru/UploadsFilesForIrbis/1f77dc9fc2f08fe5594aa6dee5793a59.pdf.Лямкина А.C., Нечунаева И.Н., Воронцова Е.В., Таирова С.А., Александрова Т.Н., Науменко О.В., Поспелова Т.И. Сравнение заболеваемости и результатов лечения хронического миелолейкоза в Новосибирске и Новосибирской области. Гематология и трансфузиология. 2023; 68(1): 35–49. doi: 10.35754/0234-5730-2023-68-1-35-49. EDN: SSLNZA.Lyamkina A.S., Nechunaeva I.N., Vorontsova E.V., Tairova S.A., Alexandrova T.N., Naumenko O.V., Pospelova T.I. Comparison of morbidity and results of chronic myeloid leukemia treatment in Novosibirsk and the Novosibirsk region. Russian Journal of Hematology and Transfusiology. 2023; 68(1): 35–49. (in Russian). doi: 10.35754/0234-5730-2023-68-1-35-49. EDN: SSLNZA.Перепечаева М.Л., Горева О.Б., Березина О.В., Поспелова Т.И., Гришанова А.Ю. miR-155 и miR-223 как маркеры клинических особенностей течения хронического лимфолейкоза. Сибирский онкологический журнал. 2024; 23(2): 75–86. doi: 10.21294/1814-4861-2024-23-1-75-86. EDN: JABBDL.Perepechaeva M.L., Goreva O.B., Berezina O.V., Pospelova T.I., Grishanova A.Yu. miR-155 and miR-223 as markers of biological and clinical features of chronic lymphocytic leukemia. Siberian Journal of Oncology. 2024; 23(1): 75–86. (in Russian). doi: 10.21294/1814-4861-2024-23-1-75-86. EDN: JABBDL.Yuan W.X., Gui Y.X., Na W.N., Chao J., Yang X. Circulating microRNA-125b and microRNA-130a expression profiles predict chemoresistance to R-CHOP in diffuse large B-cell lymphoma patients. Oncol Lett. 2016; 11(1): 423–32. doi: 10.3892/ol.2015.3866.Yuan W.X., Gui Y.X., Na W.N., Chao J., Yang X. Circulating microRNA-125b and microRNA-130a expression profiles predict chemoresistance to R-CHOP in diffuse large B-cell lymphoma patients. Oncol Lett. 2016; 11(1): 423–32. doi: 10.3892/ol.2015.3866.Liu X., Haniff H.S., Childs-Disney J.L., Shuster A., Aikawa H., Adibekian A., Disney M.D. Targeted Degradation of the Oncogenic MicroRNA 17-92 Cluster by Structure-Targeting Ligands. J Am Chem Soc. 2020; 142(15): 6970–82. doi: 10.1021/jacs.9b13159.Liu X., Haniff H.S., Childs-Disney J.L., Shuster A., Aikawa H., Adibekian A., Disney M.D. Targeted Degradation of the Oncogenic MicroRNA 17-92 Cluster by Structure-Targeting Ligands. J Am Chem Soc. 2020; 142(15): 6970–82. doi: 10.1021/jacs.9b13159.Qian Y.Y., Liu Z.S., Zhang Z., Levenson A.S., Li K. Pterostilbene increases PTEN expression through the targeted downregulation of microRNA-19a in hepatocellular carcinoma. Mol Med Rep. 2018; 17(4): 5193–201. doi: 10.3892/mmr.2018.8515.Qian Y.Y., Liu Z.S., Zhang Z., Levenson A.S., Li K. Pterostilbene increases PTEN expression through the targeted downregulation of microRNA-19a in hepatocellular carcinoma. Mol Med Rep. 2018; 17(4): 5193–201. doi: 10.3892/mmr.2018.8515.Peng C., Chen Y., Yang Z., Zhang H., Osterby L., Rosmarin A.G., Li S. PTEN is a tumor suppressor in CML stem cells and BCR-ABLinduced leukemias in mice. Blood. 2010; 115(3): 626–35. doi: 10.1182/blood-2009-06-228130.Peng C., Chen Y., Yang Z., Zhang H., Osterby L., Rosmarin A.G., Li S. PTEN is a tumor suppressor in CML stem cells and BCR-ABLinduced leukemias in mice. Blood. 2010; 115(3): 626–35. doi: 10.1182/blood-2009-06-228130.Chakraborty C., Sharma A.R., Patra B.C., Bhattacharya M., Sharma G., Lee S.S. MicroRNAs mediated regulation of MAPK signaling pathways in chronic myeloid leukemia. Oncotarget. 2016; 7(27): 42683–97. doi: 10.18632/oncotarget.7977.Chakraborty C., Sharma A.R., Patra B.C., Bhattacharya M., Sharma G., Lee S.S. MicroRNAs mediated regulation of MAPK signaling pathways in chronic myeloid leukemia. Oncotarget. 2016; 7(27): 42683–97. doi: 10.18632/oncotarget.7977.

The authors declare that there are no conflicts of interest present.