bloodjourГематология и трансфузиологияRussian journal of hematology and transfusiology0234-57302411-3042ООО Издательский дом «Практика»10.35754/0234-5730-2024-69-3-297-318bloodjour-577Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESАнализ микросателлитной нестабильности при первичной медиастинальной В-клеточной крупноклеточной лимфоме: фокус на PD-L1/PD-L2 и CIITAAnalysis of microsatellite instability in primary mediastinal large B-cell lymphoma: Focus on PD-L1/PD-L2 and CIITAhttps://orcid.org/0000-0002-5148-8355АбдурашидоваР. Р.AbdurashidovaR. R.

Абдурашидова Руниза Равильевна, гематолог отделения химиотерапии лимфатических опухолей с блоком трансплантации костного мозга и гемопоэтических стволовых клеток с дневным стационаром

125167, г. Москва

Runiza  R.  Abdurashidova*,  hematologist  of  the  Department  of  Lymphatic Tumors with Hematopoietic stem cell transplantation unit

125167, Moscow

runiza.abdurashidova@yandex.ruhttps://orcid.org/0000-0003-2957-1619РисинскаяН. В.RisinskayaN. V.

Рисинская Наталья Владимировна, кандидат биологических наук, старший научный сотрудник лаборатории молекулярной гематологии 

125167, г. Москва

Natalya  V.  Risinskaya,  Cand. Sci. (Biol.), Senior Researcher, Laboratory of Molecular Hematology

125167, Moscow

risinska@gmail.comhttps://orcid.org/0000-0003-1936-5934МангасароваЯ. К.MangasarovaY. K.

Мангасарова Яна Константиновна, кандидат медицинских наук, заведующая отделением химиотерапии лимфатических опухолей с блоком трансплантации костного мозга и гемопоэтических стволовых клеток 

125167, г. Москва

Yana K. Mangasarova, Cand. Sci. (Med), Head of the Department of Lymphatic Tumors with Hematopoietic stem cell transplantation unit

125167, Moscow

v.k.jana@mail.ruhttps://orcid.org/0000-0002-1890-4492СуринВ. Л.SurinV. L.

Сурин Вадим Леонидович, старший научный сотрудник лаборатории генной инженерии 

125167, г. Москва

Vadim L. Surin, Senior Researcher, Laboratory of Genetic Engineering

125167, Moscow

vadsurin@mail.ruhttps://orcid.org/0000-0003-0922-9314ШуплецоваИ. А.ShupletsovaI. A.

Шуплецова Ирина Александровна, кандидат медицинских наук, патологоанатом патолого-анатомического отделения 

125167, г. Москва

Irina A. Shupletsova, Cand. Sci. (Med.), Pathologist, Department of Pathology

125167, Moscow

shupletsova.i@blood.ruhttps://orcid.org/0000-0001-8044-598XЧабаеваЮ. А.ChabaevaYu. A.

Чабаева Юлия Александровна, кандидат технических наук, заместитель заведующего информационно-аналитическим отделом 

125167, г. Москва

Yuliya A. Chabaeva, Cand. Sci. (Tech.), deputy Head of the information and analytical Department

125167, Moscow

uchabaeva@gmail.comhttps://orcid.org/0000-0003-4263-8275МагомедоваА. У.MagomedovaA. U.

Магомедова Аминат Умарасхабовна, доктор медицинских наук, ведущий научный сотрудник отделения химиотерапии лимфатических опухолей с блоком трансплантации костного мозга и гемопоэтических стволовых клеток 

125167, г. Москва

Aminat U. Magomedova, Dr. Sci. (Med.), Leading Researcher of the Department of Lymphatic Tumors with a hematopoietic stem cell transplantation unit

125167, Moscow

maminat@mail.ruhttps://orcid.org/0000-0003-3163-4930АбрамоваТ. В.AbramovaT. V.

Абрамова Татьяна Валерьевна, кандидат медицинских наук, научный сотрудник лаборатории генной инженерии 

125167, г. Москва

Tatyana V. Abramova, Cand. Sci. (Med), Research associate Laboratory of Genetic Engineering

125167, Moscow

abramova.blood@gmail.comhttps://orcid.org/0000-0003-3914-8611НикулинаЕ. Е.NikulinaE. E.

Никулина Елена Евгеньевна, научный сотрудник лаборатории молекулярной гематологии 

125167, г. Москва

Elena E. Nikulina, Research associate Laboratory of Molecular Hematology

125167, Moscow

nikulina.e@blood.ruhttps://orcid.org/0009-0002-0071-898XЮсуповР. Ю.IusupovR. I.

Юсупов Расул Юсупович, студент факультета фундаментальной медицины

119991, г. Москва

Rasul  I.  Iusupov, student of medicine faculty

119991, Moscow

iusupov.iusupov@gmail.comhttps://orcid.org/0000-0002-6288-7570КуликовС. М.KulikovS. M.

Куликов Сергей Михайлович, кандидат технических наук, начальник информационно-аналитического отдела 

125167, г. Москва

Sergey M. Kulikov, Cand. Sci. (Tech.), Head of the Information and Analysis Department

125167, Moscow

smkulikov@mail.ruhttps://orcid.org/0000-0002-2639-7419ЗвонковЕ. Е.ZvonkovE. E.

Звонков Евгений Евгеньевич, доктор медицинских наук, руководитель научного отдела лимфопролиферативных заболеваний 

125167, г. Москва

Evgeny E. Zvonkov, Dr. Sci. (Med.), Head of the Department of Intensive Highdose Chemotherapy of Lymphomas

125167, Moscow

dr.zvonkov@gmail.comhttps://orcid.org/0000-0002-1082-8659КовригинаА. М.KovriginaA. M.

Ковригина Алла Михайловна, доктор биологических наук, заведующая патологоанатомическим отделением ФГБУ «Национальный медицинский исследовательский центр гематологии» Министерства здравоохранения Российской Федерации; профессор Института клинической морфологии и цифровой патологии 2 ФГАОУ ВО «Первый Московский государственный медицинский университет имени И.М. Сеченова» Министерства здравоохранения Российской Федерации (Сеченовский университет)

125167, г. Москва,

\119991, г. Москва

Alla M. Kovrigina, Dr. Sci. (Biol.), Head of the Pathology Department, National Medical Research Center for Hematology, Professor, Institute Clinical Morphology and Digital Pathology, Sechenov University

125167, Moscow,

119991, Moscow

kovrigina.alla@gmail.comhttps://orcid.org/0000-0001-9463-9187СудариковА. Б.SudarikovA. B.

Судариков Андрей Борисович, доктор биологических наук, заведующий лабораторией молекулярной гематологии 

125167, г. Москва

Andrey B. Sudarikov, Dr. Sci. (Biol.), Head of the Laboratory of Molecular Hematology

125167, Moscow

dusha@blood.ruФГБУ «Национальный медицинский исследовательский центр гематологии» Министерства здравоохранения Российской ФедерацииРоссияNational Medical Research Center for HematologyRussian FederationФГБОУ «Московский государственный университет имени М. В. Ломоносова»РоссияLomonosov Moscow State UniversityRussian FederationФГБУ «Национальный медицинский исследовательский центр гематологии» Министерства здравоохранения Российской Федерации; ФГАОУ ВО «Первый Московский государственный медицинский университет имени И.М. Сеченова» Министерства здравоохранения Российской Федерации (Сеченовский университет)РоссияNational Medical Research Center for Hematology; I.M. Sechenov First Moscow State Medical University (Sechenov University)Russian Federation202424112024693297318Copyright © Абдурашидова Р.Р., Рисинская Н.В., Мангасарова Я.К., Сурин В.Л., Шуплецова И.А., Чабаева Ю.А., Магомедова А.У., Абрамова Т.В., Никулина Е.Е., Юсупов Р.Ю., Куликов С.М., Звонков Е.Е., Ковригина А.М., Судариков А.Б., 20242024Абдурашидова Р.Р., Рисинская Н.В., Мангасарова Я.К., Сурин В.Л., Шуплецова И.А., Чабаева Ю.А., Магомедова А.У., Абрамова Т.В., Никулина Е.Е., Юсупов Р.Ю., Куликов С.М., Звонков Е.Е., Ковригина А.М., Судариков А.Б.Abdurashidova R.R., Risinskaya N.V., Mangasarova Y.K., Surin V.L., Shupletsova I.A., Chabaeva Y.A., Magomedova A.U., Abramova T.V., Nikulina E.E., Iusupov R.I., Kulikov S.M., Zvonkov E.E., Kovrigina A.M., Sudarikov A.B.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/577Введение

Введение. Первичная медиастинальная В-клеточная крупноклеточная лимфома (ПМВКЛ) — редкая неходжкинская лимфома. Учитывая иммунофенотип ПМВКЛ, отличный от диффузной В-клеточной крупноклеточной лимфомы (ДВКЛ), исследовали аберрации микросателлитных повторов (МСП) в регионах, включающих гены PD-L1/PD-L2 и CIITA.

Цель

Цель: изучить встречаемость аберраций МСП по 19 локусам панели COrDIS Plus и в регионах генов PD-L1/PD-L2, CIITA при ПМВКЛ и ДВКЛ, сопоставить с выраженностью иммуногистохимической (ИГХ) экспрессии PD-L1, HLA-DR при ПМВКЛ.

Материалы и методы

Материалы и методы. В исследование включены 137 больных, из них 86 (62,8 %) ПМВКЛ и 51 (37,2%) ДВКЛ. Проведен анализ с использованием стандартной панели COrDIS Plus, включающей набор праймеров на 19 локусов тетрануклеотидных повторов. Исследован аллельный дисбаланс (АД) МСП, ближайших к генам PD-L1/PD-L2 (9p24.1) (n = 68/86 (79,1 %) при ПМВКЛ; n = 36/51 (70,6 %) при ДВКЛ) и CIITA (16p13.13) (n = 71/86 (82,6 %) при

ПМВКЛ; n = 29/51(56,9 %) при ДВКЛ) методом STR-анализа. Больных с гомозиготным наследованием по каждому из исследуемых маркеров в отдельности в дальнейшем не включали в анализ в связи с невозможностью оценки потери гетерозиготности (loss of heterozygosity, LOH). Оценена экспрессия PD-L1 и HLA-DR иммуногистохимическим методом у 27/86 (31,4 %) больных ПМВКЛ.

Результаты

Результаты. Гомозиготность по обоим маркерам вблизи генов PD-L1/PD-L2 — у 5/68 (7,4 %) больных ПМВКЛ и 10/36 (27,8 %) ДВКЛ (р = 0,008). Аберрации МСП, фланкирующих гены PD-L1/PD-L2, были выявлены у 33/63 (52,4 %) больных ПМВКЛ и у 5/26 (19,2 %) больных ДВКЛ (р = 0,003; отношение шансов (ОШ) 5,8; 95 % доверительный интервал (ДИ) [2,8–18,7]). Гомозиготность по обоим маркерам вблизи гена CIITA была выявлена у 8/71 (11,3 %) больных ПМВКЛ и 7/29 (24,1 %) ДВКЛ (р = 0,13). АД вблизи гена CIITA выявлен у 24/63 (38,1 %) больных ПМВКЛ, в группе ДВКЛ не было изменений региона CIITA (р = 0,0001; ОШ 14,3; 95 % ДИ [2,8–262,5]). При использовании панели COrDIS Plus при ПМВКЛ и ДВКЛ частоты аберраций тетрануклеотидных повторов значимо не отличались (p = 0,78 для LOH, p = 0,17 для EMAST). Не выявлено корреляции между аберрациями МСП вблизи генов PD-L1/PD-L2 и CIITA и выраженностью экспрессии PD-L1 и HLA-DR (p = 0,402 и p = 0,668 соответственно).

Заключение

Заключение. Обнаружено значимое более частое изменение профиля МСП регионов генов PD-L1/PD-L2 и CIITA у больных ПМВКЛ по сравнению с ДВКЛ. Хромосомный микроматричный анализ в 2 из 3 случаев ПМВКЛ выявил генетические аберрации с участием генов PD-L1/PD-L2 и/или CIITA и одновременно наблюдался АД вблизи этих генов по оценке профиля МСП. Это подтверждает различный патогенез этих заболеваний и дает основание полагать, что наличие АД в указанных локусах свидетельствует о вовлеченности генов в патогенез. Отсутствовала корреляция между АД областей генов PD-L1/PD-L2 и CIITA и экспрессией PD-L1 и HLA-DR соответственно.

Introduction

Introduction. Primary mediastinal large B-cell lymphoma (PMBCL) is a rare non-Hodgkin lymphoma. Considering the immunophenotype of PMBCL, which differs from diffuse large B-cell lymphoma (DLBCL), Microsatellite Repeat (MSR) aberrations in regions flanking PD-L1/PD-L2 and CIITA genes were investigated.

Aim

Aim: to study the prevalence of MSR aberrations in 19 loci of the COrDIS Plus panel and in the regions of the PD-L1/PD-L2, CIITA genes in PMBCL and DLBCL, and to compare it with the expression level of PD-L1 and HLA-DR in PMBCL.

Materials and methods

Materials and methods. The study included 137 patients, 86 (62,8%) with PMBCL and 51 (37.2%) with DLBCL. The analysis was conducted using the standard COrDIS Plus panel, which includes a set of primers for 19 loci of tetranucleotide repeats. The allelic imbalance (AI) of MSR close to the PD-L1/PD-L2 genes (9p24.1) (n = 68/86 (79.1%) for PMBCL, n = 36/51 (70.6 %) for DLBCL) and CIITA (16p13.13) (n = 71/86 (82.6 %) for PMBCL, n = 29/51 (56.9 %) for DLBCL) was investigated using STR analysis. Patients with homozygous inheritance for each of the studied markers were excluded from further analysis due to the inability to assess loss of heterozygosity (LOH). The expression of PD-L1 and HLA-DR was assessed by immunohistochemistry in 27/86 (31.4 %) PMBCL patients.

Results

Results. Homozygosity for both markers near the PD-L1/PD-L2 genes was found in 5/68 (7.4 %) of PMBCL patients and 10/36 (27.8 %) of DLBCL patients (p = 0.008). Aberrations of MSR flanking the PD-L1/PD-L2 genes were detected in 33/63 (52.4%) of PMBCL patients and 5/26 (19.2 %) of DLBCL patients (p = 0.003; OR 5.8; 95% CI [2.8–18.7]). Homozygosity for both markers near the CIITA gene was identified in 8/71 (11.3%) of PMBCL patients and 7/29 (24.1%) of DLBCL patients (p = 0.13). AI near the CIITA gene was found in 24/63 (38.1 %) of PMBCL patients, while no changes in the CIITA region were observed in the DLBCL group (p = 0.0001; OR 14.3; 95% CI [2.8–262.5]). Using the COrDIS Plus panel, the frequencies of tetranucleotide repeat aberrations did not significantly differ between PMBCL and DLBCL (p = 0.78 for LOH, p = 0.17 for EMAST). No correlation was found between MSR aberrations near the PD-L1/PD-L2 and CIITA genes and the expression levels of PD-L1 and HLA-DR (p = 0.402 and 0.668, respectively).

Conclusion

Conclusion. A statistically significant more frequent alteration in the MSR marker profile of the PD-L1/PD-L2 and CIITA gene regions was found in PMBCL patients compared to DLBCL. Chromosomal microarray analysis in 2 out of 3 PMBCL cases revealed genetic aberrations involving the PD-L1/PD-L2 and/or CIITA genes, and AI of these genes was observed simultaneously with the MSR profile evaluation. This confirms the different pathogenesis of these diseases and suggests that the presence of AI in these loci indicates the involvement of these genes in the pathogenesis. There is no correlation between AI in the PD-L1/PD-L2 and CIITA gene regions and the expression of PD-L1 and HLA-DR, respectively.

 

 

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