Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2025; 24: 50-57
Острый мегакариобластный лейкоз с мутациями в гене GATA1 у детей без синдрома Дауна
https://doi.org/10.24287/1726-1708-2025-24-1-50-57Аннотация
Острый мегакариобластный лейкоз (ОМКЛ) составляет 4–15% детских острых миелоидных лейкозов, чаще встречаясь у детей с синдромом Дауна (СД). ОМКЛ при СД (СД-ОМКЛ) характеризуется мутациями в гене GATA1, отсутствием рекуррентных транслокаций и высокой чувствительностью к полихимиотерапии. У детей без СД ОМКЛ демонстрирует высокое генетическое разнообразие, в том числе у таких пациентов встречается биологически и клинически схожий с СД-ОМКЛ вариант ОМКЛ, также характеризующийся мутациями в гене GATA1 и отсутствием известных химерных транскриптов. Трисомия 21 носит при этом соматический характер, т. е. определяется только в лейкемических клетках. Это так называемые Даун-подобные (Down syndrome-like) ОМКЛ. С целью подробнее охарактеризовать Даун-подобные ОМКЛ мы проанализировали клиникогематологические характеристики, генетический профиль и ответ на терапию 65 пациентов с ОМКЛ без фенотипических признаков СД. Данное исследование одобрено независимым этическим комитетом и утверждено решением ученого совета ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России. Мутация в гене GATA1 была обнаружена в 14 (21%) случаях. Все 14 пациентов имели подтвержденную соматическую трисомию 21 в бластных клетках. Бластные клетки в этих случаях имели схожий с СД-ОМКЛ набор дополнительных мутаций и хромосомных аномалий. Показатели выживаемости в исследованной когорте были достоверно выше, чем у пациентов без GATA1. Таким образом, все пациенты с ОМКЛ должны быть исследованы на присутствие мутаций в гене GATA1 для более точного прогнозирования ответа на терапию.
Список литературы
1. Bhatnagar N., Nizery L., Tunstall O., Vyas P., Roberts I. Transient Abnormal Myelopoiesis and AML in Down Syndrome: an Update. Curr Hematol Malig Rep 2016; 11 (5): 333–41.
2. Masetti R., Guidi V., Ronchini L., Bertuccio N.S., Locatelli F., Pession A. The changing scenario of non-Down syndrome acute megakaryoblastic leukemia in children. Crit Rev Oncol Hematol 2019; 138: 132–8.
3. Zeller B., Gustafsson G., Forestier E., Abrahamsson J., Clausen N., Heldrup J., et al. Acute leukaemia in children with Down syndrome: a population‐based Nordic study. Br J Haematol 2005; 128 (6): 797–804.
4. Xavier A.C., Ge Y., Taub J.W. Down Syndrome and Malignancies: A Unique Clinical Relationship. J Mol Diagn 2009; 11 (5): 371–80.
5. Ravindranath Y., Abella E., Krischer J.P., Wiley J., Inoue S., Harris M., et al. Acute myeloid leukemia (AML) in Down’s syndrome is highly responsive to chemotherapy: experience on Pediatric Oncology Group AML Study 8498. Blood 1992; 80 (9): 2210–4.
6. Roy A., Cowan G., Mead A. J.,Filippi S., Bohn G., Chaidos A., et al. Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21. Proc Natl Acad Sci 2012; 109 (43): 17579–84.
7. Chou S.T., Byrska-Bishop M., Tober J.M., Yao Y., VanDorn D., Opalinska J.B., et al. Trisomy 21-associated defects in human primitive hematopoiesis revealed through induced pluripotent stem cells. Proc Natl Acad Sci 2012; 109 (43): 17573–8.
8. MacLean G.A., Menne T.F., Guo G.,Sanchez D.J., Park I.-H., Daley G.Q., et al. Altered hematopoiesis in trisomy 21 as revealed through in vitro differentiation of isogenic human pluripotent cells. Proc Natl Acad Sci 2012; 109 (43): 17567–72.
9. Orkin S.H. Diversification of haematopoietic stem cells to specific lineages. Nat Rev Genet 2000; 1 (1): 57–64.
10. Taub J.W., Matherly L.H., Stout M.L., Buck S.A., Gurney J.G., Ravindranath Y. Enhanced metabolism of 1-beta-D-arabinofuranosylcytosine in Down syndrome cells: a contributing factor to the superior event free survival of Down syndrome children with acute myeloid leukemia. Blood 1996; 87 (8): 3395– 403.
11. Frost B.-M., Gustafsson G., Larsson R.,Nygren P., Lönnerholm G. Cellular cytotoxic drug sensitivity in children with acute leukemia and Down’s syndrome: an explanation to differences in clinical outcome? Leukemia 2000; 14 (5): 943–4.
12. Zwaan C.M. Different drug sensitivity profiles of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells in children with and without Down syndrome. Blood 2002; 99 (1): 245–51.
13. Taub J.W., Ge Y. Down syndrome, drug metabolism and chromosome 21. Pediatr Blood Cancer 2005; 44 (1): 33–9.
14. Gruber T.A., Downing J.R. The biology of pediatric acute megakaryoblastic leukemia. Blood 2015; 126 (8): 943–9.
15. Hara Y., Shiba N., Ohki K., Tabuchi K., Yamato G., Park M., et al. Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non‐Down syndrome. Genes Chromosomes Cancer 2017; 56 (5): 394–404.
16. De Rooij J.D.E., Branstetter C., Ma J.,Li Y., Walsh M.P., Cheng J., et al. Pediatric non–Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes. Nat Genet 2017; 49 (3): 451–6.
17. Lopez C.K., Malinge S., Gaudry M., Bernard O.A., Mercher T. Pediatric Acute Megakaryoblastic Leukemia: Multitasking Fusion Proteins and Oncogenic Cooperations. Trends Cancer 2017; 3 (9): 631–42.
18. De Rooij J.D.E., Masetti R., Van Den Heuvel-Eibrink M.M., Cayuela J.-M., Trka J., Reinhardt D., et al. Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study. Blood 2016; 127 (26): 3424–30.
19. Popov A.M., Verzhbitskaya T.Yu., Movchan L.V., Demina I.A., Mikhailova E.V., Semchenkova A.A., et al. Flow cytometry in acute leukemia diagnostics. Guidelines of Russian-Belarusian multicenter group for pediatric leukemia studies. Pediatr Hematol Immunopathol 2023; 22 (1): 165–77.
20. Bennett J.M. Criteria for the Diagnosis of Acute Leukemia of Megakaryocyte Lineage (M7): A Report of the French-American-British Cooperative Group. Ann Intern Med 1985; 103 (3): 460.
21. Khoury J.D., Solary E., Abla O., Akkari Y., Alaggio R., Apperley J. F., et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia 2022; 36 (7): 1703–19.
22. Цаур Г.А., Ольшанская Ю.В., Обухова Т.Н., Судариков А.Б., Лазарева О.В., Гиндина Т.Л. Цитогенетическая и молекулярно-генетическая диагностика онкогематологических заболеваний: позиция Организации молекулярных генетиков в онкологии и онкогематологии. Гематология и трансфузиология 2023; 68 (1): 129–43. DOI: 10.35754/0234-57302023-68-1-129-143
23. McGowan-Jordan J., Hastings R., Moore S. Re: International System for Human Cytogenetic or Cytogenomic Nomenclature (ISCN): Some Thoughts, by T. Liehr. Cytogenet. Genome Res 2021; 161 (5): 225–6.
24. Rainis L. Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. Blood 2003; 102 (3): 981–6.
25. Den Dunnen J.T., Dalgleish R., Maglott D.R., Hart R.K., Greenblatt M.S., McGowan-Jordan J., et al. HGVS Recommendations for the Description of Sequence Variants: 2016 Update. Hum Mutat 2016; 37 (6): 564–9.
26. Quessada J., Cuccuini W., Saultier P., Loosveld M., Harrison C.J., Lafage-Pochitaloff M. Cytogenetics of Pediatric Acute Myeloid Leukemia: A Review of the Current Knowledge. Genes 2021; 12 (6): 924.
27. Yoshida K., Toki T., Okuno Y., Kanezaki R., Shiraishi Y., Sato-Otsubo A., et al. The landscape of somatic mutations in Down syndrome–related myeloid disorders. Nat Genet 2013; 45 (11): 1293–9.
28. Ono R., Hasegawa D., Hirabayashi S., Kamiya T., Yoshida, K., Yonekawa S., et al. Acute megakaryoblastic leukemia with acquired trisomy 21 and GATA1 mutations in phenotypically normal children. Eur J Pediatr 2015, 174 (4): 525–31.
29. Schweitzer J., Zimmermann M.,Rasche M., von Neuhoff C., Creutzig U., Dworzak M., et al. Improved outcome of pediatric patients with acute megakaryoblastic leukemia in the AML-BFM 04 trial. Ann Hematol 2015, 94 (8): 1327–36.
Pediatric Hematology/Oncology and Immunopathology. 2025; 24: 50-57
Pediatric non-Down syndrome acute megakaryoblastic leukemia with GATA1 mutations
https://doi.org/10.24287/1726-1708-2025-24-1-50-57Abstract
Acute megakaryoblastic leukemia (AMKL) accounts for 4–15% of childhood acute myeloid leukemia and most often affects children with Down syndrome (DS). AMKL with DS (DS-AMKL) is characterized by mutations in the GATA1 gene, the absence of recurrent translocations and high sensitivity to multi-agent chemotherapy. In children without DS, AMKL demonstrates high genetic diversity: for example, such patients can have a variant that is biologically and clinically similar to DS-AMKL and is also characterized by mutations in the GATA1 gene and the absence of known fusion transcripts. Trisomy 21 is somatic, i.e. it can be detected only in leukemic cells. This is the so-called DS-like AMKL. To better characterize DS-like AMKL, we analyzed clinical and hematological characteristics, genetic profiles, and response to therapy in 65 patients with AMKL without phenotypic features of DS. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. A mutation in the GATA1 gene was detected in 14 (21%) patients. All 14 patients had confirmed somatic trisomy 21 in blast cells. In these cases, blast cells had a profile of additional mutations and chromosomal abnormalities that was similar to DS-AMKL. Survival rates in the cohort of interest were significantly higher than in the patients without GATA1 mutations. Thus, all patients with AMKL should be tested for mutations in the GATA1 gene to more accurately predict their response to therapy.
References
1. Bhatnagar N., Nizery L., Tunstall O., Vyas P., Roberts I. Transient Abnormal Myelopoiesis and AML in Down Syndrome: an Update. Curr Hematol Malig Rep 2016; 11 (5): 333–41.
2. Masetti R., Guidi V., Ronchini L., Bertuccio N.S., Locatelli F., Pession A. The changing scenario of non-Down syndrome acute megakaryoblastic leukemia in children. Crit Rev Oncol Hematol 2019; 138: 132–8.
3. Zeller B., Gustafsson G., Forestier E., Abrahamsson J., Clausen N., Heldrup J., et al. Acute leukaemia in children with Down syndrome: a population‐based Nordic study. Br J Haematol 2005; 128 (6): 797–804.
4. Xavier A.C., Ge Y., Taub J.W. Down Syndrome and Malignancies: A Unique Clinical Relationship. J Mol Diagn 2009; 11 (5): 371–80.
5. Ravindranath Y., Abella E., Krischer J.P., Wiley J., Inoue S., Harris M., et al. Acute myeloid leukemia (AML) in Down’s syndrome is highly responsive to chemotherapy: experience on Pediatric Oncology Group AML Study 8498. Blood 1992; 80 (9): 2210–4.
6. Roy A., Cowan G., Mead A. J.,Filippi S., Bohn G., Chaidos A., et al. Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21. Proc Natl Acad Sci 2012; 109 (43): 17579–84.
7. Chou S.T., Byrska-Bishop M., Tober J.M., Yao Y., VanDorn D., Opalinska J.B., et al. Trisomy 21-associated defects in human primitive hematopoiesis revealed through induced pluripotent stem cells. Proc Natl Acad Sci 2012; 109 (43): 17573–8.
8. MacLean G.A., Menne T.F., Guo G.,Sanchez D.J., Park I.-H., Daley G.Q., et al. Altered hematopoiesis in trisomy 21 as revealed through in vitro differentiation of isogenic human pluripotent cells. Proc Natl Acad Sci 2012; 109 (43): 17567–72.
9. Orkin S.H. Diversification of haematopoietic stem cells to specific lineages. Nat Rev Genet 2000; 1 (1): 57–64.
10. Taub J.W., Matherly L.H., Stout M.L., Buck S.A., Gurney J.G., Ravindranath Y. Enhanced metabolism of 1-beta-D-arabinofuranosylcytosine in Down syndrome cells: a contributing factor to the superior event free survival of Down syndrome children with acute myeloid leukemia. Blood 1996; 87 (8): 3395– 403.
11. Frost B.-M., Gustafsson G., Larsson R.,Nygren P., Lönnerholm G. Cellular cytotoxic drug sensitivity in children with acute leukemia and Down’s syndrome: an explanation to differences in clinical outcome? Leukemia 2000; 14 (5): 943–4.
12. Zwaan C.M. Different drug sensitivity profiles of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells in children with and without Down syndrome. Blood 2002; 99 (1): 245–51.
13. Taub J.W., Ge Y. Down syndrome, drug metabolism and chromosome 21. Pediatr Blood Cancer 2005; 44 (1): 33–9.
14. Gruber T.A., Downing J.R. The biology of pediatric acute megakaryoblastic leukemia. Blood 2015; 126 (8): 943–9.
15. Hara Y., Shiba N., Ohki K., Tabuchi K., Yamato G., Park M., et al. Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non‐Down syndrome. Genes Chromosomes Cancer 2017; 56 (5): 394–404.
16. De Rooij J.D.E., Branstetter C., Ma J.,Li Y., Walsh M.P., Cheng J., et al. Pediatric non–Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes. Nat Genet 2017; 49 (3): 451–6.
17. Lopez C.K., Malinge S., Gaudry M., Bernard O.A., Mercher T. Pediatric Acute Megakaryoblastic Leukemia: Multitasking Fusion Proteins and Oncogenic Cooperations. Trends Cancer 2017; 3 (9): 631–42.
18. De Rooij J.D.E., Masetti R., Van Den Heuvel-Eibrink M.M., Cayuela J.-M., Trka J., Reinhardt D., et al. Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study. Blood 2016; 127 (26): 3424–30.
19. Popov A.M., Verzhbitskaya T.Yu., Movchan L.V., Demina I.A., Mikhailova E.V., Semchenkova A.A., et al. Flow cytometry in acute leukemia diagnostics. Guidelines of Russian-Belarusian multicenter group for pediatric leukemia studies. Pediatr Hematol Immunopathol 2023; 22 (1): 165–77.
20. Bennett J.M. Criteria for the Diagnosis of Acute Leukemia of Megakaryocyte Lineage (M7): A Report of the French-American-British Cooperative Group. Ann Intern Med 1985; 103 (3): 460.
21. Khoury J.D., Solary E., Abla O., Akkari Y., Alaggio R., Apperley J. F., et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia 2022; 36 (7): 1703–19.
22. Tsaur G.A., Ol'shanskaya Yu.V., Obukhova T.N., Sudarikov A.B., Lazareva O.V., Gindina T.L. Tsitogeneticheskaya i molekulyarno-geneticheskaya diagnostika onkogematologicheskikh zabolevanii: pozitsiya Organizatsii molekulyarnykh genetikov v onkologii i onkogematologii. Gematologiya i transfuziologiya 2023; 68 (1): 129–43. DOI: 10.35754/0234-57302023-68-1-129-143
23. McGowan-Jordan J., Hastings R., Moore S. Re: International System for Human Cytogenetic or Cytogenomic Nomenclature (ISCN): Some Thoughts, by T. Liehr. Cytogenet. Genome Res 2021; 161 (5): 225–6.
24. Rainis L. Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. Blood 2003; 102 (3): 981–6.
25. Den Dunnen J.T., Dalgleish R., Maglott D.R., Hart R.K., Greenblatt M.S., McGowan-Jordan J., et al. HGVS Recommendations for the Description of Sequence Variants: 2016 Update. Hum Mutat 2016; 37 (6): 564–9.
26. Quessada J., Cuccuini W., Saultier P., Loosveld M., Harrison C.J., Lafage-Pochitaloff M. Cytogenetics of Pediatric Acute Myeloid Leukemia: A Review of the Current Knowledge. Genes 2021; 12 (6): 924.
27. Yoshida K., Toki T., Okuno Y., Kanezaki R., Shiraishi Y., Sato-Otsubo A., et al. The landscape of somatic mutations in Down syndrome–related myeloid disorders. Nat Genet 2013; 45 (11): 1293–9.
28. Ono R., Hasegawa D., Hirabayashi S., Kamiya T., Yoshida, K., Yonekawa S., et al. Acute megakaryoblastic leukemia with acquired trisomy 21 and GATA1 mutations in phenotypically normal children. Eur J Pediatr 2015, 174 (4): 525–31.
29. Schweitzer J., Zimmermann M.,Rasche M., von Neuhoff C., Creutzig U., Dworzak M., et al. Improved outcome of pediatric patients with acute megakaryoblastic leukemia in the AML-BFM 04 trial. Ann Hematol 2015, 94 (8): 1327–36.
