Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2024; 23: 102-115
Дополнительные генетические аберрации, выявляемые методом флуоресцентной гибридизации in situ, у детей с острым лимфобластным лейкозом и транслокацией t(12;21)(p13;q22)/ETV6::RUNX1: связь с инициальными клинико-лабораторными показателями и ответом на терапию
https://doi.org/10.24287/1726-1708-2024-23-3-102-115Аннотация
Транслокация t(12;21)(p13;q22)/ETV6::RUNX1 является одной из наиболее частых генетических аберраций при остром лимфобластном лейкозе из В-линейных предшественников (BПОЛЛ) у детей. Данная транслокация часто сочетается с изменением числа копий аллей генов ETV6 и RUNX1. Технология флуоресцентной гибридизации in situ (FISH), которая широко применяется для выявления t(12;21)(p13;q22), также позволяет детектировать и эти дополнительные генетические аберрации (FISH-паттерны). Целью данной работы являлась детальная характеристика FISH-паттернов у пациентов с ВП-ОЛЛ и наличием транслокации t(12;21)(p13;q22)/ETV6::RUNX1. В работу включен 241 пациент с t(12;21)позитивным ОЛЛ, которым было проведено исследование методом FISH с использованием двухцветного флуоресцентного зонда с двойным слиянием в период с 2008 по 2023 г. Данное исследование одобрено независимым этическим комитетом и утверждено решением ученого совета ГАУЗ СO «Институт медицинских клеточных технологий» (Екатеринбург). Единственный FISH-паттерн (моноклональные случаи) был выявлен в 200 (83,0%) случаях, 2 паттерна и более (поликлональные случаи) – в 41 (17,0%). Среди последних подавляющее большинство (n = 39; 95,1%) имели по 2 паттерна. Наиболее распространенным вторичным генетическим изменением оказалась делеция ETV6 (n = 105; 43,5%). Несколько реже выявляли дополнительную копию RUNX1 (n = 97; 40,2%), сочетание делеции ETV6 и дополнительной копии RUNX1 (n = 27; 11,2%), а также дополнительную копию ETV6 (n = 5; 2,0%). Доля пациентов с одним FISHпаттерном, который не содержал дополнительных генетических изменений и был следствием стандартной реципрокной транслокации (2F1G1R), оказалась относительно небольшой (n = 35; 17,5%). Были выявлены 5 прогностически неблагоприятных FISH-паттернов, ассоциированных с высоким риском рецидива. В их число входили случаи с одновременным наличием дополнительных копий ETV6 и RUNX1 (паттерн 2F2G2R), а также с изолированными дополнительными копиями RUNX1 (паттерн 2F2R-3F2R) или ETV6 (паттерн 1F1G2R-2F2G4R), частичной делецией ETV6 (паттерн 2F1Gdim1R) и нереципрокной транслокацией t(12;21) (паттерн 1F1R-1F1G1R). Объединение этих прогностически неблагоприятных FISH-паттернов в 1 группу позволило спрогнозировать 6 (46%) из 13 рецидивов, развившихся у пациентов, включенных в анализ, за исследуемый период. Важно подчеркнуть, что доля пациентов с неблагоприятными FISH-паттернами и инициальным лейкоцитозом выше 30 × 109/л достоверно не отличалась от остальной группы пациентов. Еще одним важным наблюдением являлось то, что пациенты с прогностически неблагоприятными FISH-паттернами хорошо отвечали на индукционную терапию как по данным цитологического исследования крови и костного мозга на 8, 15 и 36-й дни терапии, так и по результатам определения минимальной остаточной болезни на момент окончания индукционной терапии по протоколу ALL-MB 2015. Сравнение паттернов на этапах первичной диагностики и диагностики рецидива показало, что только 6 (50%) из 12 оцениваемых случаев, которым было проведено FISH-исследование в обеих точках наблюдения, сохранили стабильность. Таким образом, ВП-ОЛЛ с транслокацией t(12;21)(p13;q22)/ETV6::RUNX1 характеризуется большим разнообразием вторичных генетических вариантов, выявляемых с помощью метода FISH, наиболее частой из которых является делеция ETV6. Выявленная нами группа прогностически неблагоприятных FISН-паттернов требует дальнейшего изучения на большей когорте пациентов в целях возможной их рестратификации для более интенсивного лечения.
Список литературы
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2. Wiemels J.L., Cazzaniga G., Daniotti M., Eden O.B., Addison G.M., Masera G., et al. Prenatal origin of acute lymphoblastic leukaemia in children. Lancet 1999; 354: 1499–503.
3. Lausten-Thomsen U., Madsen H.O., Vestergaard T.R., Hjalgrim H., Nersting J., Schmiegelow K. Prevalence of t(12;21)[ETV6-RUNX1]-positive cells in healthy neonates. Blood 2011; 117: 186–9.
4. Stams W.A., Beverloo H.B., den Boer M.L., de Menezes R.X., Stigter R.L., van Drunen E., et al. Incidence of additional genetic changes in the TEL and AML1 genes in DCOG and COALL-treated t(12;21)-positive pediatric ALL, and their relation with drug sensitivity and clinical outcome. Leukemia 2006; 20 (3): 410–6.
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6. De Braekeleer E., Douet-Guilbert N., Morel F., Le Bris M.-J., Férec C., De Braekeleer M. RUNX1 translocations and fusion genes in malignant hemopathies. Future Oncol 2011; 7 (1): 77–91.
7. Sood R., Kamikubo Y., Liu P. Role of RUNX1 in hematological malignancies. Blood 2017; 129 (15): 2070–82.
8. Fuka G., Kauer M., Kofler R., Haas O.A., Panzer-Grümayer R. The leukemia-specific fusion gene ETV6/RUNX1 perturbs distinct key biological functions primarily by gene repression. PLoS One 2011; 6: 26348.
9. Sun C., Chang L., Zhu X. Pathogenesis of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia and mechanisms underlying its relapse. Oncotarget 2017; 8: 35445–59.
10. Sundaresh A., Gasparoli L., Mangolini M., Edwards D., Hubank M., Brooks T., et al. Aberrant transcriptional pathways in t (12; 21) Acute Lymphoblastic Leukemia. Klinische Pädiatrie 2016; 228: A12.
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14. Cave H., Cacheux V., Raynaud S., Brunie G., Bakkus M., Cochaux P., et al. ETV6 is the target of chromosome 12p deletions in t(12;21) childhood acute lymphocytic leukemia. Leukemia 1997; 11: 1459–64.
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Pediatric Hematology/Oncology and Immunopathology. 2024; 23: 102-115
Additional genetic aberrations detected by fluorescence in situ hybridization in children with acute lymphoblastic leukemia and the t(12;21)(p13;q22)/ETV6::RUNX1 translocation: an association with initial clinical and laboratory findings and response to therapy
https://doi.org/10.24287/1726-1708-2024-23-3-102-115Abstract
Translocation t(12;21)(p13;q22)/ETV6::RUNX1 is among the most common genetic aberrations in pediatric B-cell precursor acute lymphoblastic leukekian (BCP-ALL). This translocation is often combined with ETV6 and/or RUNX1 copy number variations. Fluorescence in situ hybridization (FISH) technique, which is widely used to reveal the presence of t(12;21)(p13;q22), also allows the detection of these additional genetic aberrations (FISH patterns). The aim of this study was to provide detailed characteristics of FISH patterns in patients with BCP-ALL and the t(12;21)(p13;q22)/ETV6::RUNX1 translocation. In our study we enrolled 241 patients with t(12;21)-positive ALL who had undergone testing with a dual-color double-fusion FISH assay between 2008 and 2023. This study was approved by the Independent Ethics Committee and the Academic Council of the Research Institute of Medical Cell Technologies (Ekaterinburg). A single FISH pattern (monoclonal cases) was identified in 200 patients (83.0%), 2 or more patterns (polyclonal cases) were detected in 41 (17.0%) patients. The majority of polyclonal cases (n = 39; 95.1%) exhibited 2 patterns. The most common secondary genetic alteration was ETV6 deletion (n = 105; 43.5%). Less common aberrations included an additional copy of RUNX1 (n = 97; 40.2%), a combination of ETV6 deletion and an additional copy of RUNX1 (n = 27; 11.2%), and an additional copy of ETV6 (n = 5; 2.0%). The number of the patients with one FISH pattern that did not contain any additional genetic aberrations as a result of a reciprocal translocation (2F1G1R) was relatively small (n = 35; 17.5%). We identified 5 prognostically unfavorable FISH patterns associated with a high risk of relapse. These included cases with simultaneous presence of ETV6 and RUNX1 additional copies (pattern 2F2G2R), isolated additional copies of RUNX1 (pattern 2F2R-3F2R) or ETV6 (pattern 1F1G2R-2F2G4R), a partial deletion of ETV6 (pattern 2F1Gdim1R) and a non-reciprocal translocation of t(12;21) (pattern 1F1R-1F1G1R). Grouping these unfavorable prognostic FISH patterns together made it possible to predict 6 (46%) out of 13 relapses that occurred in the patients during the study period. It is important to highlight that the number of the patients with unfavorable FISH patterns and initial leukocytosis of > 30 × 109 leukocytes/L did not differ significantly from the rest of the group. Another important observation was that the patients with prognostically unfavorable FISH patterns responded well to induction therapy, as assessed both by cytological examination of blood and bone marrow smears on days 8, 15, and 36 of therapy and by MRD response at the end of induction therapy according to the ALL-MB 2015 protocol. A comparison of FISH patterns detected at initial diagnosis and at relapse showed that only 6 (50%) out of 12 cases who had undergone FISH testing at both time points remained stable. In conclusion, BCP-ALL with the translocation t(12;21)(p13;q22)/ETV6::RUNX1 was characterized by a vast variety of secondary genetic aberrations detected by FISH, the most prevalent of which was ETV6 deletion. A group of unfavorable FISH patterns identified in our study warrants further investigation in a larger cohort of ALL patients for their possible re-stratification so that they could receive more intensive treatment.
References
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3. Lausten-Thomsen U., Madsen H.O., Vestergaard T.R., Hjalgrim H., Nersting J., Schmiegelow K. Prevalence of t(12;21)[ETV6-RUNX1]-positive cells in healthy neonates. Blood 2011; 117: 186–9.
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6. De Braekeleer E., Douet-Guilbert N., Morel F., Le Bris M.-J., Férec C., De Braekeleer M. RUNX1 translocations and fusion genes in malignant hemopathies. Future Oncol 2011; 7 (1): 77–91.
7. Sood R., Kamikubo Y., Liu P. Role of RUNX1 in hematological malignancies. Blood 2017; 129 (15): 2070–82.
8. Fuka G., Kauer M., Kofler R., Haas O.A., Panzer-Grümayer R. The leukemia-specific fusion gene ETV6/RUNX1 perturbs distinct key biological functions primarily by gene repression. PLoS One 2011; 6: 26348.
9. Sun C., Chang L., Zhu X. Pathogenesis of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia and mechanisms underlying its relapse. Oncotarget 2017; 8: 35445–59.
10. Sundaresh A., Gasparoli L., Mangolini M., Edwards D., Hubank M., Brooks T., et al. Aberrant transcriptional pathways in t (12; 21) Acute Lymphoblastic Leukemia. Klinische Pädiatrie 2016; 228: A12.
11. Fuka G., Kantner H.P., Grausenburger R., Inthal A., Bauer E., Krapf G., et al. Silencing of ETV6/ RUNX1 abrogates PI3K/AKT/mTOR signaling and impairs reconstitution of leukemia in xenografts. Leukemia 2012; 26: 927–33.
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15. Peter A., Heiden T., Taube T., Körner G., Seeger K. Interphase FISH on TEL/AML1 positive acute lymphoblastic leukemia relapses--analysis of clinical relevance of additional TEL and AML1 copy number changes. Eur J Haematol 2009; 83: 420–32.
16. Fears S., Vignon C., Bohlander S.K., Smith S., Rowley J.D., Nucifora G. Correlation between the ETV6/ CBFA2 (TEL/AML1) fusion gene and karyotypic abnormalities in children with B-cell precursor acute lymphoblastic leukemia. Genes Chromosomes Cancer 1996; 17: 127–35.
17. Sawinska M., Ladon D. Mechanism, detection and clinical significance of the reciprocal translocation t(12;21) (p12;q22) in the children suffering from acute lymphoblastic leukaemia. Leuk Res 2004; 28: 35–42.
18. Harada H., Harada Y. Point mutations in the AML1/RUNX1 gene associated with myelodysplastic syndrome. Crit Rev Eukaryot Gene Expr 2005; 15 (3): 183–96.
19. Bhojwani D., Pei D., Sandlund J.T., Jeha S., Ribeiro R.C., Rubnitz J.E., et al. ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy. Leukemia 2012; 2 (26): 265–70.
20. Moorman A.V., Ensor H.M., Richards S.M., Chilton L., Schwab C., Kinsey S.E., et al. Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial. Lancet Oncol 2010; 11 (5): 429–38.
21. Borst L., Wesolowska A., Joshi T., Borup R., Nielsen F.C., Andersen M.K., et al. Genome-wide analysis of cytogenetic aberrations in ETV6/RUNX1-positive childhood acute lymphoblastic leukaemia. Br J Haematol 2012; 157: 476–82.
22. Bokemeyer A., Eckert C., Meyr F., Koerner G., von Stackelberg A., Ullmann R., et al. Copy number genome alterations are associated with treatment response and outcome in relapsed childhood ETV6/ RUNX1-positive acute lymphoblastic leukemia. Haematologica 2014; 99: 706–14.
23. Hunger S.P., Mullighan C.G. Acute Lymphoblastic Leukemia in Children. New Engl J Med 2015; 373 (16): 1541–52.
24. Roberts K.G., Mullighan C.G. Genomics in acute lymphoblastic leukaemia: insights and treatment implications. Nat Rev Clin Oncol 2015; 12: 344–57.
25. Greaves M.F., Maia A.T., Wiemels J.L., Ford A.M. Leukemia in twins: lessons in natural history. Blood 2003; 102: 2321.
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