bloodjourГематология и трансфузиологияRussian journal of hematology and transfusiology0234-57302411-3042ООО Издательский дом «Практика»10.35754/0234-5730-2019-64-3-362-374bloodjour-154Research ArticleКЛИНИЧЕСКИЕ НАБЛЮДЕНИЯCASE REPORTSСРАВНЕНИЕ МОЛЕКУЛЯРНО-ГЕНЕТИЧЕСКОЙ СТРУКТУРЫ ОПУХОЛЕВЫХ КЛЕТОК ДО ЛЕЧЕНИЯ И ПОСЛЕ КОНСТАТАЦИИ РЕЦИДИВА МНОЖЕСТВЕННОЙ МИЕЛОМЫ (КРАТКИЙ ОБЗОР И ОПИСАНИЕ КЛИНИЧЕСКОГО СЛУЧАЯ)MOLECULAR GENETIC STRUCTURE OF MULTIPLE MYELOMA TUMOUR CELLS PRIOR TO TREATMENT AND AT THE TIME OF RELAPSE: SHORT REVIEW AND CASE REPORThttps://orcid.org/0000-0003-4863-4902СергееваА. М.SergeevaA. M.

научный сотрудник лаборатории генной инженерии,

125167, г. Москва, Новый Зыковский проезд, 4

Researcher, Laboratory of Genetic Engineering,

125167, Moscow

curleww@gmail.comhttps://orcid.org/0000-0003-3163-4930АбрамоваТ. В.AbramovaT. V.

кандидат медицинских наук, врач клинической лабораторной диагностики лаборатории кариологии,

125167, Москва

Cand. Sci. (Med.), Pathologist, Laboratory of Karyology,

125167, Moscow

abramova.blood@gmail.comhttps://orcid.org/0000-0002-1890-4492СуринВ. Л.SurinV. L.

старший научный сотрудник лаборатории генной инженерии,

125167, Москва

Senior Researcher, Laboratory of Genetic Engineering,

125167, Moscow

vadsurin@mail.ruhttps://orcid.org/0000-0003-1613-652XОбуховаТ. Н.ObukhovaT. N.

кандидат медицинских наук, заведующая лабораторией кариологии,

125167, Москва

Senior Researcher, Laboratory of Genetic Engineering,

125167, Moscow

obukhova_t@mail.ruhttps://orcid.org/0000-0002-6082-0110ДовыденкоМ. В.DovydenkoM. V.

кандидат медицинских наук, врач-гематолог отделения интенсивной высокодозной химиотерапии и трансплантации костного мозга с круглосуточным стационаром,

125167, Москва

Cand. Sci. (Med.), Hematologist, Department of Intensive High-dose Chemotherapy and Bone Marrow Transplantation,

125167, Moscow

nareyko@yandex.ruhttps://orcid.org/0000-0002-1890-4492СунцоваМ. В.SuntsovaM. V.

младший научный сотрудник лаборатории геномного анализа сигнальных систем клетки,

117198, Москва;

117997, Москва

Junior Researcher, Laboratory for the Genomic Analysis of Cell Signaling Systems,

117198, Moscow;

117997, Moscow

suntsova@oncobox.comhttps://orcid.org/0000-0001-9866-3424БуздинА. А.BuzdinA. A.

доктор медицинских наук, профессор, заведующий лабораторией клинической и геномной биоинформатики,

117997, Москва;

119991, Москва

Dr. Sci. (Med.), Prof., Head of the Laboratory for Clinical and Genomic Bioinformatics,

117997, Moscow;

119991, Moscow

buzdin@oncobox.comhttps://orcid.org/0000-0002-4966-8146МенделееваЛ. П.MendeleevaL. P.

доктор медицинских наук, профессор, заведующая отделением высокодозной химиотерапии парапротеинемических гемобластозов,

125167, Москва

Dr. Sci. (Med.), Prof., Head of the Department of Highdose Chemotherapy for Paraproteinemic Hemoblastoses,

125167, Moscow

Mendeleeva.L@blood.ruФГБУ «Национальный медицинский исследовательский центр гематологии» Министерства здравоохранения Российской ФедерацииРоссияNational Research Center for HematologyRussian FederationФГБУН «Институт биоорганической химии им. академиков М.М. Шемякина и Ю.А. Овчинникова» Российской академии наук; ФГБУ «Федеральный научно-клинический центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева» Министерства здравоохранения Российской ФедерацииРоссияShemyakin & Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences; Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and ImmunologyRussian FederationФГБУ «Федеральный научно-клинический центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева» Министерства здравоохранения Российской Федерации; ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» (Сеченовский университет) Министерства здравоохранения Российской ФедерацииРоссияDmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology; I.M. Sechenov First Moscow State Medical University (Sechenov University)Russian Federation201909112019643362374Copyright © Сергеева А.М., Абрамова Т.В., Сурин В.Л., Обухова Т.Н., Довыденко М.В., Сунцова М.В., Буздин А.А., Менделеева Л.П., 20192019Сергеева А.М., Абрамова Т.В., Сурин В.Л., Обухова Т.Н., Довыденко М.В., Сунцова М.В., Буздин А.А., Менделеева Л.П.Sergeeva A.M., Abramova T.V., Surin V.L., Obukhova T.N., Dovydenko M.V., Suntsova M.V., Buzdin A.A., Mendeleeva L.P.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.htjournal.ru/jour/article/view/154Введение

Введение. Множественная миелома (ММ) является лимфопролиферативным заболеванием, длительность ремиссии которого сложно прогнозировать.

Цель работы

Цель работы: проанализировать молекулярно-генетический статус опухоли у больного с коротким периодом ремиссии в дебюте и рецидиве ММ и сопоставить с клиническим течением заболевания.

Материалы и методы

Материалы и методы. Соматические мутации определяли методом секвенирования по Сэнгеру. Уровень экспрессии генов анализировали с помощью секвенирования РНК на платформе Illumina. Для изучения хромосомных перестроек проводили флуоресцентную гибридизацию in situ (FISH-исследование).

Результаты

Результаты. До начала лечения и в рецидиве заболевания у больного выявлена гетерозиготная клональная мутация с.182A>C (p.Q61P) в гене N-RAS, нарушающая регуляцию сигнального пути МАРК. Транскриптомный анализ, выполненный методом RNA-seq, показал резкое усиление экспрессии гена IL6 при рецидиве (в 30 раз), которое могло послужить пусковым механизмом прогрессии множественной миеломы, поскольку этот цитокин стимулирует клеточную пролиферацию, активируя различные сигнальные пути (MAPK, JAK-STAT, PI3K). Прогрессия заболевания сопровождалась также усилением экспрессии ключевых регуляторных генов (с-MYC, Notch2, MDM, RAF1, STAT4, mTOR) и резким уменьшением экспрессии генов иммуноглобулинов, вызвавшим у больного глубокий иммунодефицит. При молекулярно-цитогенетическом исследовании (FISH) в дебюте заболевания была выявлена трисомия по хромосомам 5, 9, и 15. Рецидив заболевания сопровождался амплификацией локуса 1q21 при сохранении гипердиплоидии.

Заключение

Заключение. Для прогноза длительности периода ремиссии необходимо проводить комплексный молекулярногенетический скрининг. 

Introduction

Introduction. Multiple myeloma (MM) is a lymphoproliferative disorder, for which the duration of remission is hard to predict.

Aim

Aim. To analyse the molecular genetic status of the tumour of MM patient with a short remission period at the onset and relapse of the disease, as well as to conduct its comparison with the clinical course of the disease.

Materials and methods

Materials and methods. Somatic mutations were detected through Sanger sequencing. The level of gene expression was analysed using RNA sequencing on the Illumina platform. In order to study chromosomal rearrangements, the authors performed fluorescence hybridisation in situ (FISH study).

Results

Results. Prior to the treatment and during the relapse of the disease, the patient revealed a heterozygous clonal mutation p.182A>C (p.Q61P) in the N-RAS gene, which is known to hamper regulation of the MAPK signalling pathway. The transcriptome analysis performed using the RNA-seq method revealed a sharp increase in the expression of the IL6 gene during relapse (by 30 times), which could have served as a trigger for the progression of multiple myeloma, given that this cytokine stimulates cell proliferation by activating various signalling pathways (MAPK, JAK- STAT, PI3K). The progression of the disease was also accompanied by an increased expression of key regulatory genes (с-MYC, Notch2, MDM, RAF1, STAT4, mTOR) and a sharp decrease in the expression of immunoglobulin genes, which caused deep immunodeficiency in the patient. A molecular cytogenetic study (FISH) revealed trisomy of chromosomes 5, 9 and 15 at the onset of the disease. Disease relapse occurred with the amplification of the 1q21 locus, with hyperdiploidy being preserved.

Conclusion

Conclusion. In order to predict the duration of the remission period, a complex molecular genetic screening is required. 

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