ОБЗОРЫ

Использование достижений современных геномных технологий при лимфомах

ОБЗОРЫ , , , ,

М.В. Немцова1, М.В. Майорова2

1 Российская медицинская академия последипломного образования Минздрава России, ул. Баррикадная, д. 2/1, Москва, Российская Федерация, 125993

2 Московский научно-исследовательский онкологический институт им. П.А. Герцена, 2-й Боткинский пр-д, д. 3, Москва, Российская Федерация, 125284

Для переписки: Марина Вячеславовна Немцова, д-р биол. наук, профессор, ул. Баррикадная, д. 2/1, Москва, Российская Федерация, 125993; тел.: +7(499)252-21-04; e-mail: nemtsova_m_v@mail.ru

Для цитирования: Немцова М.В., Майорова М.В. Использование достижений современных геномных технологий при лимфомах. Клиническая онкогематология. 2016;9(3):265-70.

DOI: 10.21320/2500-2139-2016-9-3-265-270

РЕФЕРАТ

Современные достижения в области геномики и биологии рака позволили значительно расширить объем знаний о молекулярном патогенезе лимфом. С использованием полногеномных методов исследования и современных компьютерных технологий удалось доказать, что разнообразные гистологические и иммуноморфологические подтипы лимфом различаются на молекулярном уровне и возникают в результате действия различных онкогенных механизмов. Стало понятно, что в основе вариабельности клинических симптомов, которые наблюдаются у пациентов с лимфомами, лежат как гетерогенность опухолевых клеток, так и особенности молекулярного патогенеза. Основываясь на полученных данных, предложены стратегии для разработки новых препаратов, которые сегодня используются в лечении лимфом. Они включают определение молекулярных этапов патогенеза, оценку значимости каждого этапа для развития опухоли и получение препарата с направленным действием на этот этап. В результате предложено несколько новых классов молекулярных таргетных агентов для лечения лимфом, которые сегодня изучаются в клинических исследованиях. В современную эпоху персонализированной медицины одной из основных задач при лечении пациентов с лимфомами является определение правильной таргетной терапии для каждого типа лимфоидной опухоли, характеризующейся уникальными молекулярными механизмами опухолеобразования.

Ключевые слова: лимфомы, профиль экспрессии генов, микроРНК, сигнальные пути, NF-kB.

Получено: 13 февраля 2016 г.

Принято в печать: 14 марта 2016 г.

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Гиперэкспрессия гена WT1 при злокачественных опухолях системы крови: теоретические и клинические аспекты (обзор литературы)

ОБЗОРЫ , , ,

Н.Н. Мамаев, Я.В. Гудожникова, А.В. Горбунова

НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой, ГБОУ ВПО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова» Минздрава России, ул. Льва Толстого, д. 6/8, Санкт-Петербург, Российская Федерация, 197022

Для переписки: Николай Николаевич Мамаев, д-р мед. наук, профессор, ул. Льва Толстого, д. 6/8, Санкт-Петербург, Российская Федерация, 197022; тел.: +(7)911-760-50-86; e-mail: nikmamaev524@gmail.com

Для цитирования: Мамаев Н.Н., Гудожникова Я.В., Горбунова А.В. Гиперэкспрессия гена WT1 при злокачественных опухолях системы крови: теоретические и клинические аспекты (обзор литературы). Клиническая онкогематология. 2016;9(3):257-64.

DOI: 10.21320/2500-2139-2016-9-3-257-264

РЕФЕРАТ

В статье обсуждаются полученные в последние годы данные о феномене гиперэкспрессии гена WT1 у пациентов с острыми лейкозами, миелодиспластическими синдромами, хроническим миелолейкозом, неходжкинскими лимфомами и множественной миеломой. Показана большая перспективность мониторинга уровня экспрессии гена WT1 в посттрансплантационный период и после индукционной химиотерапии. Такой подход может использоваться в диагностике минимальной остаточной болезни и раннем выявлении рецидивов лейкозов, а также для их своевременного и контролируемого лечения. Из других исследовательских направлений представляется перспективным тестирование аутотрансплантата на наличие или отсутствие в нем опухолевых элементов, а также оценка эффективности индукционной терапии у больных из группы повышенного прогностического риска.

Ключевые слова: феномен гиперэкспрессии гена WT1, трансплантация гемопоэтических стволовых клеток, химиотерапия, молекулярный мониторинг лечения.

Получено: 8 февраля 2016 г.

Принято в печать: 30 марта 2016 г.

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Мутации генов при острых миелоидных лейкозах

ОБЗОРЫ , , , , ,

О.В. Блау

Клиника Шарите, Берлинский медицинский университет, ул. Хинденбургдамм, д. 30, Берлин, Германия, 12200

Для переписки: Ольга Владимировна Блау, д-р мед. наук, Department of Hematology, Oncology and Tumorimmunology, Charite University School of Medicine, Hindenburgdamm 30, 12200, Berlin, Germany; e-mail: olga.blau@charite.de.

Для цитирования: Блау О.В. Мутации генов при острых миелоидных лейкозах. Клиническая онкогематология. 2016;9(3):245-56.

DOI: 10.21320/2500-2139-2016-9-3-245-256

РЕФЕРАТ

Острый миелобластный лейкоз (ОМЛ) — клональное злокачественное заболевание, характеризующееся неэффективным гемопоэзом. Большинство больных ОМЛ имеют различные цитогенетические и молекулярно-генетические повреждения, которые сочетаются с определенными биологическими и клиническими особенностями заболевания. Примерно у 50–60 % больных de novo и у 80–95 % больных вторичными ОМЛ обнаруживаются хромосомные изменения. Следует отметить, что структурные цитогенетические аберрации являются наиболее частыми маркерами и встречаются примерно в 40 % случаев ОМЛ de novo. Достаточно большая группа больных с нормальным кариотипом (НК-ОМЛ), формально относящаяся к категории промежуточного риска, является крайне гетерогенной в отношении прогноза течения заболевания. В действующие прогностические классификации ОМЛ включены сегодня только некоторые мутации, характеризующиеся известным прогностическим значением, в частности NPM1, FLT3 и C/EBPa. Пациенты с NPM1, но без мутаций FLT3-ITD или с мутациями C/EBPa характеризуются благоприятным прогнозом заболевания, а с мутацией FLT3-ITD — неблагоприятным. Недавно выявлен новый класс мутаций, при которых повреждаются гены, ответственные за эпигенетические процессы регуляции генома, в частности метилирование ДНК или модификацию гистонов. Среди них наиболее изученными к настоящему времени являются мутации в генах DNMT3A, IDH1/2, TET2 и некоторых других. В целом ряде исследований показан неблагоприятный прогностический эффект мутации DNMT3A при ОМЛ. Что касается прогностического значения IDH1/2, то данный вопрос еще не до конца ясен. На прогноз заболевания влияет ряд биологических факторов, в т. ч. сочетание с цитогенетическими аберрациями и другими мутациями, особенно FLT3 и NPM1. Число исследований, посвященных генетическим мутациям при ОМЛ, постоянно растет. Накопленные к настоящему времени знания о генетических изменениях при ОМЛ подтверждают их роль в возникновении и развитии заболевания.

Ключевые слова: острый миелобластный лейкоз, ОМЛ, кариотип, цитогенетические аберрации, мутации генов, прогноз.

Получено: 23 января 2016 г.

Принято в печать: 4 апреля 2016 г.

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Моноклональные антитела: от создания до клинического применения

ОБЗОРЫ , , , ,

Ю.И. Будчанов

ГБОУ ВПО «Тверской медицинский университет», ул. Советская, д. 4, Тверь, Российская Федерация, 170000

Для переписки: Юрий Иванович Будчанов, 1-й пер. Красной Слободы, д. 3, Тверь, Российская Федерация, 170001; e-mail: budjur@mail.ru

Для цитирования: Будчанов Ю.И. Моноклональные антитела: от создания до клинического применения. Клиническая онкогематология. 2016;9(3):237-44.

DOI: 10.21320/2500-2139-2016-9-3-237-244

РЕФЕРАТ

Создание моноклональных антител (МКА) привело к революционным достижениям в диагностике и лечении онкогематологических заболеваний. В обзоре рассматриваются история создания, новые улучшенные технологии получения моноклональных антител на примере анти-CD20-МКА, распознающих различные эпитопы антигена CD20 и обладающих повышенной противоопухолевой активностью. Инженерные модификации должны помочь понять эффекторные механизмы использования новых анти-CD20-МКА и направлены на дальнейшее улучшение результатов лечения.

Ключевые слова: моноклональные антитела, ритуксимаб, офатумумаб, обинутузумаб, гибридомная технология.

Получено: 13 января 2016 г.

Принято в печать: 17 марта 2016 г.

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Истинная полицитемия: новая концепция диагностики и клинические формы

ОБЗОРЫ , , ,

А.М. Ковригина1, В.В. Байков2

1 ФГБУ «Гематологический научный центр» Минздрава России, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167

2 НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой, ГБОУ ВПО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова» Минздрава России, ул. Рентгена, д. 12, Санкт-Петербург, Российская Федерация, 197022

Для переписки: Алла Михайловна Ковригина, д-р биол. наук, профессор, Новый Зыковский пр-д., д. 4а, Москва, Российская Федерация, 125167; тел.: +7(495)612-61-12; e-mail: kovrigina.alla@gmail.com

Для цитирования: Ковригина А.М., Байков В.В. Истинная полицитемия: новая концепция диагностики и клинические формы. Клиническая онкогематология. 2016;9(2):115–22.

DOI: 10.21320/2500-2139-2016-9-2-115-122

РЕФЕРАТ

Истинная полицитемия (ИП) — клональное Ph-негативное миелопролиферативное заболевание с избыточной пролиферацией 3 ростков кроветворения и исходом в стадию неэффективного миелопоэза. В классификации ВОЗ (2008) показатели гемоглобина и гематокрита включены в главные критерии диагностики заболевания. Однако у многих пациентов с ИП уровень этих показателей может оказаться ниже диагностического, что приводит к гиподиагностике данного заболевания. В настоящее время выделены три клинических формы болезни: 1) маскированная (латентная/продромальная), 2) классическая (развернутая), 3) ИП с прогрессированием/трансформацией в миелофиброз. Маскированная ИП наиболее сложна для диагностики. Она гетерогенна по клинико-лабораторным данным, анамнезу, течению заболевания; включает в себя ранние стадии, в т. ч. с высоким тромбоцитозом, имитирующие эссенциальную тромбоцитемию, случаи с абдоминальными тромбозами, а также длительно латентно протекающую ИП. Наиболее информативным способом диагностики маскированной формы ИП является исследование трепанобиоптата костного мозга. Обычно выявляется классическая картина ИП: гиперклеточный костный мозг с трехростковой пролиферацией миелопоэза, пролиферация мегакариоцитов со слабой или умеренно выраженной атипией и полиморфизмом клеток. Определение степени ретикулинового фиброза имеет важное прогностическое значение и отражает риск прогрессии/трансформации в миелофиброз. В новой редакции классификации ВОЗ (2016) морфологическое исследование трепанобиоптата костного мозга будет введено в большие критерии диагностики ИП в качестве обязательного при пограничных значениях уровня гемоглобина и гематокрита.

Ключевые слова: истинная полицитемия, миелопролиферативное заболевание, диагностика истинной полицитемии, формы истинной полицитемии.

Получено: 19 января 2016 г.

Принято в печать: 1 февраля 2016 г.

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ЛИТЕРАТУРА

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Вирус Эпштейна—Барр и классическая лимфома Ходжкина

ОБЗОРЫ , , , , ,

В.Э. Гурцевич

ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» Минздрава России, Каширское ш., д. 24, Москва, Российская Федерация, 115478

Для переписки: Владимир Эдуардович Гурцевич, д-р мед. наук, профессор, Каширское ш., д. 24, Москва, Российская Федерация, 115478; тел.: +7(499)324-25-64; e-mail: gurvlad532@yahoo.com

Для цитирования: Гурцевич В.Э. Вирус Эпштейна—Барр и классическая лимфома Ходжкина. Клиническая онкогематология. 2016;9(2):101–14.

DOI: 10.21320/2500-2139-2016-9-2-101-114

РЕФЕРАТ

Среди онкогенных вирусов человека вирус Эпштейна—Барр (ВЭБ) обращает на себя внимание уникальными свойствами. Этот широко распространенный среди населения планеты вирус одновременно является лидером по числу ассоциированных с ним различных доброкачественных и злокачественных новообразований лимфоидного и эпителиального происхождения. Онкогенный потенциал ВЭБ связан с его способностью инфицировать и трансформировать лимфоциты человека. В тех случаях, когда взаимодействие между размножением ВЭБ, его латентным состоянием и иммунным контролем со стороны организма нарушается, создаются условия для длительной пролиферации инфицированных ВЭБ лимфоцитов и их злокачественной трансформации. По мнению ряда исследователей, молекулярные механизмы связанного с ВЭБ канцерогенеза обусловлены способностью вирусного генома стимулировать экспрессию серии продуктов, имитирующих ряд факторов роста, транскрипции и оказывающих антиапоптотическое действие. Эти кодируемые ВЭБ продукты нарушают сигнальные пути, которые регулируют различные клеточные функции гомеостаза, наделяя клетку способностью к неограниченной пролиферации. Тем не менее точный механизм, с помощью которого ВЭБ инициирует онкогенез, остается не до конца выясненным. В обзоре приводится обобщающая информация о структуре и онкогенном потенциале ВЭБ, морфологических и клинических вариантах лимфомы Ходжкина (ЛХ), а также роли ВЭБ в патогенезе связанных с этим вирусом вариантов ЛХ. Кроме того, в обзоре освещены последние данные об использовании уровня вирусной ДНК ВЭБ в плазме больных ЛХ в качестве биомаркера, отражающего эффективность проведенного лечения и прогноз болезни.

Ключевые слова: вирус Эпштейна—Барр, ВЭБ, латентный мембранный белок 1, LMP1, лимфома Ходжкина, копии ДНК ВЭБ.

Получено: 5 февраля 2016 г.

Принято в печать: 8 февраля 2016 г.

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Метаболизм железа в норме и при патологии

ОБЗОРЫ , , , , ,

Е.А. Лукина, А.В. Деженкова

ФГБУ «Гематологический научный центр» Минздрава России, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167

Для переписки: Елена Алексеевна Лукина, д-р мед. наук, профессор, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167; тел.: +7(495)612-09-23; e-mail: elenalukina02@gmail.com

Для цитирования: Лукина Е.А., Деженкова А.В. Метаболизм  железа в норме и при патологии. Клиническая онкогематология. 2015;8(4):355–361.

DOI: 10.21320/2500-2139-2015-8-4-355-361

РЕФЕРАТ

В обзоре изложены современные представления о физиологической и патологической роли железа, а также основных механизмах регуляции метаболизма железа в организме человека. В последние годы показано, что не только дефицит, но и избыток данного микроэлемента имеют катастрофические последствия для организма, а содержание данного микроэлемента жестко регулируется, что позволяет говорить о гомеостазе железа. Из общего количества железа (3–5 г), содержащегося в организме здорового человека, основная часть входит в состав клеток крови, костного мозга и печени и находится в связанном с белками состоянии, что необходимо для предотвращения цитотоксических эффектов свободных ионов железа. В обзоре приводится краткая информация об основных белках, участвующих в метаболизме железа, и их роли в поддержании гомеостаза данного микроэлемента. Особое внимание уделяется функциональному значению гепсидина, играющего ключевую роль в регуляции внеклеточного содержания железа, и процессам рециркуляции железа. Приводится краткая информация о механизмах развития функционального дефицита железа и его роли в патогенезе анемии хронических заболеваний. Существенное внимание уделяется характеристике состояния перегрузки железом, способам диагностики и средствам коррекции вторичного гемохроматоза.

Ключевые слова: метаболизм железа, ферритин, гепсидин, рециркуляция железа, анемия хронических заболеваний, перегрузка железом.

Получено: 1 июля 2015 г.

Принято в печать: 9 ноября 2015 г.

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Роль экспрессии c-MYC, BCL2 и BCL6 в патогенезе диффузной В-крупноклеточной лимфомы

ОБЗОРЫ

А.Е. Мисюрина1, В.А. Мисюрин2, Е.А. Барях1, А.М. Ковригина1, С.К. Кравченко1

1 ФГБУ «Гематологический научный центр» МЗ РФ, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167

2 ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина», Каширское ш., д. 24, Москва, Российская Федерация, 115478

Для переписки: А.Е. Мисюрина, аспирант, Новый Зыковский проезд, д. 4а, Москва, Российская Федерация, 125167; тел.: +7(909)637-32-49; e-mail: anna.lukina1@gmail.com

Для цитирования: Мисюрина А.Е., Мисюрин В.А., Барях Е.А., Ковригина А.М., Кравченко С.К. Роль экспрессии генов c-MYC, BCL2 и BCL6 в патогенезе диффузной В-крупноклеточной лимфомы. Клин. онкогематол. 2014; 7(4): 512–521.

РЕФЕРАТ

Согласно современным представлениям, опирающимся на результаты исследования профиля экспрессии генов, существует несколько подтипов диффузной B-крупноклеточной лимфомы (ДBКЛ): из В-клеток герминативного центра и из активированных В-клеток. Гены c-MYC, BCL6 и BCL2 являются ключевыми регуляторами развития В-лимфоцитов на уровне герминальной (фолликулярной) дифференцировки. В патогенезе ДВКЛ наиболее часто играют роль генетические аномалии с их участием. От общего уровня активности и механизмов, приводящих к гиперэкспрессии каждого из этих генов и продукции соответствующих белков, зависит прогноз заболевания. Мы предполагаем, что определение количественных параметров экспрессии генов c-MYC, BCL6 и BCL2, а также кодируемых ими белков позволит с высокой точностью выделять группы риска среди больных ДBКЛ.

Ключевые слова: диффузная В-крупноклеточная лимфома, молекулярные подтипы, группы риска, c-MYC, BCL6, BCL2.

Принято в печать: 8 сентября 2014 г.

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Биология ниши гемопоэтических стволовых клеток

ОБЗОРЫ , , ,

Н.Ю. Семенова, С.С. Бессмельцев, В.И. Ругаль

ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии» ФМБА РФ, 2-я Советская ул., д. 16, Санкт-Петербург, Российская Федерация, 191024

Для переписки: С.С. Бессмельцев, д-р мед. наук, профессор, 2-я Советская ул., д. 16, Санкт-Петербург, Российская Федерация, 191024; тел.: +7(812)717-67-80; e-mail: bsshem@hotmail.com

Для цитирования: Семенова Н.Ю., Бессмельцев С.С., Ругаль В.И. Биология ниши гемопоэтических стволовых клеток. Клин. онкогематол. 2014; 7(4): 501–510.

РЕФЕРАТ

В статье представлены современные данные о роли стромальной ниши костного мозга в регуляции гемопоэтических стволовых клеток (ГСК). Отражены этапы формирования концепции гемопоэтической ниши. Дана характеристика стромальных клеточных элементов, образующих нишу, и освещены механизмы регуляции ГСК. Обсуждаются вопросы роли ниши в лейкозной трансформации ГСК. Представлены сведения о структурных изменениях ниши при нарушении развития ГСК.

Ключевые слова: гемопоэтические стволовые клетки, костный мозг, ниша гемопоэтических стволовых клеток, микроокружение.

Принято в печать: 1 сентября 2014 г.

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Альтернативное кровоснабжение в костном мозге при онкогематологических заболеваниях

ОБЗОРЫ , ,

А.А. Вартанян

ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина», Каширское ш., д. 24, Москва, Российская Федерация, 115478

Для переписки: А.А. Вартанян, д-р биол. наук, ст. науч. сотрудник, Каширское ш., д. 24, Москва, Российская Федерация, 115478; тел.: +7(499)324-10-65; e-mail: zhivotov57@mail.ru

Для цитирования: Вартанян А.А. Альтернативное кровоснабжение в костном мозге при онкогематологических заболеваниях. Клин. онкогематол. 2014; 7(4): 491–500.

РЕФЕРАТ

Неоангиогенез, или формирование новых микрососудов на основе уже существующей в ткани сети сосудов, является необходимым условием для роста опухоли. Долгое время неоангиогенез считали единственной возможностью доставки в опухоль питательных веществ и кислорода. В последние годы рассматриваются также альтернативные механизмы васкуляризации опухоли. Формирование высокоструктурированных васкулярных каналов из опухолевых клеток в отсутствие эндотелиальных клеток и фибробластов, ограниченных базальной мембраной, или васкулогенная мимикрия (ВМ), сегодня рассматривается как дополнительная система кровоснабжения опухоли. ВМ обнаружена практически во всех опухолях, и ее появление ассоциируется с плохим прогнозом. В настоящем обзоре суммированы основные характеристики ВМ в солидных опухолях и при онкогематологических заболеваниях. Обсуждается также значение указанного феномена в диагностике опухолей и в прогнозировании их течения.

Ключевые слова: неоангиогенез, васкулогенная мимикрия, онкогематологические заболевания.

Принято в печать: 1 сентября 2014 г.

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