Молекулярно-биологические характеристики мышиного перевиваемого миелопролиферативного заболевания тема диссертации и автореферата по ВАК РФ 14.01.21, кандидат биологических наук Бигильдеев, Алексей Евгеньевич

• Бигильдеев, Алексей Евгеньевич
• кандидат биологических наук
• 2010

Оглавление диссертации кандидат биологических наук Бигильдеев, Алексей Евгеньевич

ОГЛАВЛЕНИЕ.

Основные обозначения и сокращения.'.

ВВЕДЕНИЕ.

Введение диссертации (часть автореферата) на тему «Молекулярно-биологические характеристики мышиного перевиваемого миелопролиферативного заболевания»

цель работы.8

Основные задачи.8

Научная новизна и практическое значение работы.8

Материалы и методы исследования.9

Основные положения, выносимые на защиту.9

Содержание работы по главам.10

Благодарности.10

Заключение диссертации по теме «Гематология и переливание крови», Бигильдеев, Алексей Евгеньевич

выводы

1. Охарактеризован уникальный перевиваемый миелоидный лейкоз, сходный с миелопролиферативным заболеванием, с элементами гистиоцитарной саркомы.

2. Лейкоз переносится гетерогенной популяцией стволовых клеток, несущих на поверхности маркеры кроветворных клеток разной степени зрелости.

3. При этом заболевании происходит заселение костного мозга лейкозными клетками, но основная масса опухолевых клеток, представленная клетками, несущими поверхностные маркеры и экспрессирующими специфические гены моноцитов/макрофагов и гранулоцитов, локализуется экстрамедуллярно в печени заболевших животных.

4. По мере развития заболевания в печени нарастает количество CD45 положительных опухолевых клеток, что приводит к быстрой гибели животных от печеночной недостаточности.

5. Опухолевые клетки несут на поверхности рецепторы к хемокинам и цитокинам, секретируемым печенью, что играет важную роль в заселении этого органа клетками данного лейкоза.

6. Концентрация лейкозных стволовых клеток среди клеток, инвазирующих печень, на 2 порядка выше, чем в костном мозге терминально больных животных.

7. В лейкозных клетках значительно повышена экспрессия многих онкогенов, генов, отвечающих за самоподдержание, пролиферацию, адгезию к субстрату и генов-рецепторов к хемокинам, которые синтезируются в печени.

8. Гены сигнального пути транскрипционного фактора NF-KappaB, являющегося одним из важных маркеров, отличающих стволовые клетки опухоли от нормальных стволовых кроветворных клеток, активированы в лейкозных клетках данного заболевания.

9. Для изучения механизмов опухолевой трансформации получена хорошо ' охарактеризованная оригинальная модель, отличающаяся гетерогенностью лейкозных стволовых клеток и высоким сродством опухолевых клеток к печени.

По данной теме были опубликованы следующие печатные работы:

1. А Е. Бигильдеев, Н.В.Сац, А.Л.Грищук, И.Н.Нифонтова, Д.А.Свинарева, Н.И.Дризе, 2008. Характеристика перевиваемого мышиного миелопролиферативного заболевания, развившегося после многократных введений гранулоцитарного колониестимулирующего фактора. Бюлл.экспер.биол.мед., т.145, №2,—234-238.

2. И.Н.Шипунова, А.Е.Бигильдеев., Н.В.Сац, Д.А.Свинарева, Т.В.Тодрия, И.Л.Чертков, В.Г.Савченко, Н.И.Дризе, 2008. Влияние длительного воздействия гранулоцитарного колониестимулирующего фактора (г-ксф) на кроветворение. Гематология и трансфузиология, т.53, №5, стр. 63-67.

3. А.Е. Бигильдеев, И.Н. Шипунова, Д.А. Свинарева, Т.В. Петрова, Т.В. Тодрия, Т.В. Васильева, Н.И. Дризе, 2009. Изучение динамики развития перевиваемого миелопролиферативного заболевания мыши, развившегося после нескольких курсов введения гранулоцитарного колониестимулирующего фактора. Гематол. и трансфузиол., т.54, № 5, стр. 3-8.

4. Шипунова (Нифонтова) И.Н., Бигильдеев А.Е., Свинарева Д.А., Дризе Н.И., 2010. Характеристики лейкозных стволовых клеток мышиного миелопролиферативного заболевания, поражающего печень. Бюлл.экспер.биол.мед., т.148, №3, стр.265-270.

5. A.Grishchuk, A.Bigildeev, LNifontova, D.Svinareva, N.Drize, V.Savchenko. Alterations in gene expression in murine leukemia cells developed after G-CSF treatement, 2006. Hematologica/The hematology journal,,vol.91 (si), p316, abst.0859.

6. A.Bigildeev, A.L.Grishchuk,N.V.Saz, I.N.Nifontova,D.A.Svinareva,N.J.Drize, 2007. Analysis of gene expression pattern in bone marrow and liver of mice developed myeloproliferative disease after long-term G-CSF treatement. Hematologica/The hematology journal, vol.92(sl), p489, abst.1358.

7. A.E.Bigildeev, A.L.Grishchuk, N.V.Sats, I.N.Nifontova, D.A.Svinareva, N.J.Drize, 2007. Characteriazation of gene expression in malignant hematopoietic cells invading the liver of mice developed transplantable myeloproliferative disease. Experimental Hematology, vol.35, number 9, suppl.2, p.70, abst. P089.

8. A.E.Bigildeev, I.N.Nifontova, D.A.Svinareva, N.V.Sats, N.J.Drize, 2008. Analysis of hematopoietic precursor cells and gene expression pattern in malignant cells of mice developed myeloproliferative disease after G-CSF treatment. Experimental Hematology, 2008, vol.36, №7, suppl.l, p.35 (P029).

9. A.E.Bigildeev, I.N.Nifontova, T.V.Todria, N.J.Drize, 2008. Dynamics of leukemia development on murine model of myeloproliferative disorder. Mechanisms of early differentiation: embryogenesis, myogenesis and hematopoiesis/lymphopoiesis, September 1-5,2008, Barsinghausen, Germany, p.84, abs.2.

10. A.E.Bigildeev, I.N.Shipounova, D.A.Svinareva, N.J.Drize, 2009. Murine myeloproliferative disorder with liver lesion: characteristics of leukemia stem cells and phenotype of cells invaded liver. Hematologica/The hematology journal, June 2009, vol.94 (s2), p. 356 (abstr.884)

11.A.E. Bigildeev, I.N. Shipounova, D.A. Svinareva, N.J. Drize, 2009. Cell Population Highly Enriched with LSCs Invades Liver in MPD-Like Myeloid Leukemia. Blood (ASH Annual Meeting Abstracts), Nov; 114: abs. 4569.

12. A.E.Bigildeev, N.J.Drize, I.N.Shipounova, D.A.Svinareva, 2009. Characteristics of leukemia stem cells in murine myeloproliferative disorder with liver lesion. Experimental Hematology, 2009, vol.37, №9, suppl.l, p.50 (P063).

13. A. Bigildeev, I. Shipounova, D. Svinareva, N. Drize, 2010. The dynamics of the formation of extranodal leukemia metastasis in the liver leading to acute liver failure in mice. Cellular Oncology/Analytical cellular pathology, vol.32, №3, p.227.

14. A. Bigildeev, N.Drize, 2010 Leukemia stem cells (LSCs) invading liver in the murine MPD-like myeloid leukemia with liver lesion: Molecular characteristics. Hematologica/The hematology journal, vol.95(s2), p599, abst.1507.

Заключение

Таким образом, были изучены молекулярно биологические характеристики мышиного перевиваемого лейкоза. Установлено, что развитие после многократного введения животным Г-КСФ лейкоза непосредственно не связано с введением этого ростового фактора. Рецептор Г-КСФ на клетках КМ и печени не содержит мутаций и не изменена экспрессия генов, кодирующих основные молекулы его сигнального пути.

Были охарактеризованы ЛСК этого гемобластоза. Показано, что стволовые клетки этой опухоли организуют иерархию, сходную с иерархией нормальных СКК. На каждой ступени иерархии опухолевые клетки сохраняют способность к самоподдержанию и переносу заболевания. По мере продвижения от ранних к более поздним клеткам-предшественникам лейкоза частота встречаемости ЛСК в популяции увеличивается. Максимальная частота ЛСК наблюдается среди клеток, инвазирующих печень, которые несут специфические маркеры моноцитарного ростка. Такое устройство иерархии в отделе ЛСК описано впервые при этом заболевании.

Исследованное заболевание является уникальной моделью перевиваемого лейкоза, поражающего печень. Исследована динамика развития заболевания в печени и показано, что пролиферация опухолевых клеток в ней является причиной гибели животных от гепатотоксичности. Подробно охарактеризованы резидентные опухолевые клетки в печени. Выяснены возможные причины и механизмы заселения печени опухолевыми клетками, связанные с экспрессией специфических хемокинов и их рецепторов на опухолевых клетках.

Изучение механизмов лейкозогенеза на уровне экспрессии генов выявило несколько групп генов с измененной экспрессией. К ним относятся: транскрипционные факторы, включая онкогены, молекулы адгезии, цитокины и, что особенно важно, гены «домашнего хозяйства». Полученные результаты демонстрируют принципиальные изменения в биологии опухолевых клеток, затрагивающие большинство их физиологических параметров.

Можно заключить, что это заболевание является важной и перспективной моделью для дальнейшего изучения процессов лейкозогенеза, свойств ЛСК и образования метастазов (заселения и пролиферации опухолевых клеток в экстрамедуллярной ткани).

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