Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2021; 20: 46-53
Иммунофенотипическая характеристика острого миелоидного лейкоза с inv(16)(p13.1q22)/t(16;16) (p13.1;q22)/CBFb-MYH11 у детей
Михайлова Е. В., Кашпор С. А., Зеркаленкова Е. А., Семченкова А. А., Дубровина М. Э., Ольшанская Ю. В., Плясунова С. А., Калинина И. И., Масчан М. А., Масчан А. А., Новичкова Г. А., Попов А. М.
https://doi.org/10.24287/1726-1708-2021-20-1-46-53Аннотация
Целью данной работы было изучение иммунофенотипа клеток острого миелоидного лейкоза (ОМЛ) с inv(16)(p13.1q22)/CBFb-MYH11 и t(16;16)(p13.1;q22)/CBFb-MYH11 у детей. Данное исследование одобрено независимым этическим комитетом и утверждено решением ученого совета ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России. Проанализированы образцы костного мозга 36 детей с впервые выявленным ОМЛ с inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFb-MYH11. Была выявлена крайняя гетерогенность иммунофенотипа опухолевых клеток: экспрессировались как антигены ранних стадий дифференцировки (CD34, CD117, CD123), так и маркеры зрелых моноцитов (CD11c, CD14, CD64) и нейтрофилов (CD65, CD15). При этом в 55,6% случаев была отмечена коэкспрессия маркеров других линий дифференцировки, наиболее частым из которых был лимфоидный антиген CD2. В 83,3% исследуемых образцов отмечалось разделение популяции на 2 части: более «незрелую» – миелобластную, экспрессирующую ранние маркеры дифференцировки (CD34, CD117), и более «дифференцированную» – несущую на своей поверхности маркеры зрелых моноцитов (CD11b, CD14, CD33). При этом четкой границы между данными частями провести невозможно. Несмотря на то, что моноцитарная часть опухолевой популяции иммунофенотипически схожа с нормальными моноцитами, в 87,5% случаев ОМЛ с CBFb-MYH11 отмечалось наличие коэкспрессии тех же маркеров лимфоидной дифференцировки, что и на опухолевых миелобластах. Кроме того, было показано, что в лейкемических моноцитах детектируется химерный транскрипт CBFb-MYH11 на уровне, сопоставимом с таковым в лейкемических бластах. Наличие данных особенностей у моноцитов позволяет считать их частью опухолевой популяции и учитывать их иммунофенотип при описании суммарного иммунофенотипа опухоли при ОМЛ.
Список литературы
1. Norris D., Stone J. WHO classification of tumours of haematopoietic and lymphoid tissues. Geneva: WHO; 2008; 22–23.
2. Arber D.A., Orazi A., Hasserjian R., Thiele J., Borowitz M.J., Le Beau M.M. et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127 (20): 2391–405.
3. Liu P., Tarle S.A., Hajra A., Claxton D.F., Marlton P., Freedman M. et al. Fusion between transcription factor CBF beta/ PEBP2 beta and a myosin heavy chain in acute myeloid leukemia. Science 1993; 261 (5124): 1041–4.
4. Bain B.J., Bene M.C. Morphological and immunophenotypic clues to the WHO categories of acute myeloid leukaemia. Acta haematologica 2019; 141 (4): 232– 44.
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6. Delaunay J., Vey N., Leblanc T., Fenaux P., Rigal-Huguet F., Witz F. et al. Prognosis of inv(16)/t(16; 16) acute myeloid leukemia (AML): a survey of 110 cases from the French AML Intergroup. Blood 2003; 102 (2): 462–9.
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16. van Solinge T.S., Zeijlemaker W., Ossenkoppele G.J., Cloos J., Schuurhuis G.J. The interference of genetic associations in establishing the prognostic value of the immunophenotype in acute myeloid leukemia. Cytometry B Clin Cytom 2018; 94 (1): 151–8.
17. Perea G., Domingo A., Villamor N., Palacios C., Junca J., Torres P. et al. Adverse prognostic impact of CD36 and CD2 expression in adult de novo acute myeloid leukemia patients. Leukemia research 2005; 29 (10): 1109–16.
18. Mauvieux L., Delabesse E., Bourquelot P., Radford-Weiss I., Bennaceur A., Flandrin G. et al. NG2 expression in MLL rearranged acute myeloid leukaemia is restricted to monoblastic cases. British journal of haematology 1999; 107 (3): 674–6.
19. Попов А.М., Цаур Г.А., Вержбицкая Т.Ю., Стренева О.В., Шориков Е.В., Савельев Л.И. и др. Иммунофенотипическая характеристика острого миелоидного лейкоза у детей первого года жизни. Онкогематология 2013; 1: 33–9.
20. Zerkalenkova E., Mikhaylova E., Lebedeva S., Illarionova O., Baidun L., Kashpor S. et al. Quantifi cation of NG2‐positivity for the precise prediction of KMT2A gene rearrangements in childhood acute leukemia. Genes Chromosomes Cancer 2021; 60 (2): 88–99. DOI: 10.1002/gcc.22915
21. Haferlach T., Winkemann M., Loffler H., Schoch R., Gassmann W., Fonatsch C. et al. The abnormal eosinophils are part of the leukemic cell population in acute myelomonocytic leukemia with abnormal eosinophils (AML M4Eo) and carry the pericentric inversion 16: a combination of May-Grunwald-Giemsa staining and fl uorescence in situ hybridization. Blood 1996; 87 (6): 2459–63.
22. Basso G., Buldini B., De Zen L., Orfao A. New methodologic approaches for immunophenotyping acute leukemias. Haematologica 2001; 86 (7): 675–92.
23. Creutzig U., van den Heuvel-Eibrink M.M., Gibson B., Dworzak M.N., Adachi S., de Bont E. et al. Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel. Blood 2012; 120 (16): 3187–205.
Pediatric Hematology/Oncology and Immunopathology. 2021; 20: 46-53
Immunophenotypic characterization of pediatric acute myeloid leukemia with inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFb-MYH11
Mikhailova E. V., Kashpor S. A., Zerkalenkova E. A., Semchenkova A. A., Dubrovina M. E., Plyasunova S. A., Olshanskaya Yu. V., Kalinina I. I., Maschan M. A., Maschan A. A., Novichkova G. A., Popov A. M.
https://doi.org/10.24287/1726-1708-2021-20-1-46-53Abstract
The aim of this study was to describe the immunophenotype of leukemic cells in acute myeloid leukemia (AML) with inv(16) (p13.1q22)/CBFb-MYH11 and t(16;16)(p13.1;q22)/CBFb-MYH11 in children. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. We investigated bone marrow samples from 36 pediatric patients with initially diagnosed AML with inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFb-MYH11. Immunophenotypic profile of leukemic cells was very heterogeneous: cells expressed antigens of early stages of differentiation (CD34, CD117, CD123) as well as markers of mature monocytes (CD11c, CD14, CD64) and neutrophils (CD65, CD15). Moreover, in 55.6% of cases lymphoid coexpressions were noticed (CD2 – the most frequent one). Furthermore, in 83.3% of cases we detected the separation of leukemic cells population into two parts: more “immature” – myeloblastic, which expressed early markers of differentiation (CD34, CD117), and more “mature” part, expressing monocytic antigens (CD11b, CD14, CD33). There was no clear separation between these parts of population. Despite the immunophenotypic similarity between monocytic part of leukemic population and normal monocytes, in 87.5% of studied cases there were same lymphoid coexpressions on these cells as on leukemic myeloblasts. Moreover, we showed that levels of CBFb-MYH11 expression in leukemic monocytes and myeloblasts were comparable. Presence of these characteristics in monocytes allows to consider them as part of leukemic cells population and take into consideration during the total immunophenotype reporting.
References
1. Norris D., Stone J. WHO classification of tumours of haematopoietic and lymphoid tissues. Geneva: WHO; 2008; 22–23.
2. Arber D.A., Orazi A., Hasserjian R., Thiele J., Borowitz M.J., Le Beau M.M. et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127 (20): 2391–405.
3. Liu P., Tarle S.A., Hajra A., Claxton D.F., Marlton P., Freedman M. et al. Fusion between transcription factor CBF beta/ PEBP2 beta and a myosin heavy chain in acute myeloid leukemia. Science 1993; 261 (5124): 1041–4.
4. Bain B.J., Bene M.C. Morphological and immunophenotypic clues to the WHO categories of acute myeloid leukaemia. Acta haematologica 2019; 141 (4): 232– 44.
5. Bolouri H., Farrar J.E., Triche Jr.T., Ries R.E., Lim E.L., Alonzo T.A. et al. The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions. Nature medicine 2018; 24 (1): 103–12.
6. Delaunay J., Vey N., Leblanc T., Fenaux P., Rigal-Huguet F., Witz F. et al. Prognosis of inv(16)/t(16; 16) acute myeloid leukemia (AML): a survey of 110 cases from the French AML Intergroup. Blood 2003; 102 (2): 462–9.
7. Buldini B., Maurer-Granofszky M., Varotto E., Dworzak M.N. Flow-cytometric monitoring of minimal residual disease in pediatric patients with acute myeloid leukemia: recent advances and future strategies. Front Pediatr 2019; 7: 412. DOI: 10.3389/fped.2019.00412
8. Bene M.C., Castoldi G., Knapp W., Ludwig W.D., Matutes E., Orfao A. et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia 1995; 9 (10): 1783–6.
9. Gonggrijp H.S., Augustinus E., Leeksma C.H. Hot bands: a simple G-banding method for leukemic metaphases. Cancer genetics and cytogenetics 1985; 15 (3–4): 373–4.
10. McGowan-Jordan J., Simons A., Schmid M. ISCN 2016: An international system for human cytogenomic nomenclature Karger: Basel; 2016.
11. Gabert J., Beillard E., Van der Velden V.H.J., Bi W., Grimwade D., Pallisgaard N. et al. Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – a Europe Against Cancer program. Leukemia 2003; 17 (12): 2318–57.
12. Lambert C., Preijers F.W., Yanikkaya Demirel G., Sack U. Monocytes and macrophages in fl ow: an ESCCA initiative on advanced analyses of monocyte lineage using fl ow cytometry. Cytometry Part B: Clinical Cytometry 2017; 92 (3): 180–8.
13. Von Neuhoff C., Reinhardt D., Sander A., Zimmermann M., Bradtke J., Betts D.R. et al. Prognostic impact of specific chromosomal aberrations in a large group of pediatric patients with acute myeloid leukemia treated uniformly according to trial AML-BFM 98. J Clin Oncol 2010; 28 (16): 2682–9.
14. Voigt A.P., Brodersen L.E., Alonzo T.A., Gerbing R.B., Menssen A.J., Wilson E.R. et al. Phenotype in combination with genotype improves outcome prediction in acute myeloid leukemia: a report from Children’s Oncology Group protocol AAML0531. Haematologica 2017; 102 (12): 2058–68.
15. Adriaansen H.J., Te Boekhorst P.A., Hagemeijer A.M., van der Schoot C.E., Delwel H.R., van Dongen J.J. Acute myeloid leukemia M4 with bone marrow eosinophilia (M4Eo) and inv(16)(p13q22) exhibits a specific immunophenotype with CD2 expression. Blood 1993; 81 (11): 3043– 51.
16. van Solinge T.S., Zeijlemaker W., Ossenkoppele G.J., Cloos J., Schuurhuis G.J. The interference of genetic associations in establishing the prognostic value of the immunophenotype in acute myeloid leukemia. Cytometry B Clin Cytom 2018; 94 (1): 151–8.
17. Perea G., Domingo A., Villamor N., Palacios C., Junca J., Torres P. et al. Adverse prognostic impact of CD36 and CD2 expression in adult de novo acute myeloid leukemia patients. Leukemia research 2005; 29 (10): 1109–16.
18. Mauvieux L., Delabesse E., Bourquelot P., Radford-Weiss I., Bennaceur A., Flandrin G. et al. NG2 expression in MLL rearranged acute myeloid leukaemia is restricted to monoblastic cases. British journal of haematology 1999; 107 (3): 674–6.
19. Popov A.M., Tsaur G.A., Verzhbitskaya T.Yu., Streneva O.V., Shorikov E.V., Savel'ev L.I. i dr. Immunofenotipicheskaya kharakteristika ostrogo mieloidnogo leikoza u detei pervogo goda zhizni. Onkogematologiya 2013; 1: 33–9.
20. Zerkalenkova E., Mikhaylova E., Lebedeva S., Illarionova O., Baidun L., Kashpor S. et al. Quantifi cation of NG2‐positivity for the precise prediction of KMT2A gene rearrangements in childhood acute leukemia. Genes Chromosomes Cancer 2021; 60 (2): 88–99. DOI: 10.1002/gcc.22915
21. Haferlach T., Winkemann M., Loffler H., Schoch R., Gassmann W., Fonatsch C. et al. The abnormal eosinophils are part of the leukemic cell population in acute myelomonocytic leukemia with abnormal eosinophils (AML M4Eo) and carry the pericentric inversion 16: a combination of May-Grunwald-Giemsa staining and fl uorescence in situ hybridization. Blood 1996; 87 (6): 2459–63.
22. Basso G., Buldini B., De Zen L., Orfao A. New methodologic approaches for immunophenotyping acute leukemias. Haematologica 2001; 86 (7): 675–92.
23. Creutzig U., van den Heuvel-Eibrink M.M., Gibson B., Dworzak M.N., Adachi S., de Bont E. et al. Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel. Blood 2012; 120 (16): 3187–205.
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