Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2025; 24: 58-65
Прогностическое значение природы гена-партнера и локализации точки разрыва у детей с KMT2A-позитивным острым миелоидным лейкозом
https://doi.org/10.24287/1726-1708-2025-24-1-58-65Аннотация
Острый миелоидный лейкоз (ОМЛ) с перестройками гена KMT2A является одним из наиболее частых вариантов ОМЛ у детей. Перестройки гена KMT2A представляют собой крайне гетерогенную группу, что обусловлено различной локализацией разрыва в ДНК данного гена в сочетании с большим количеством различных генов-партнеров. Пациентов с KMT2A-позитивным ОМЛ традиционно относят к группе высокого риска, однако в отечественной и международной литературе имеются данные о различном прогностическом значении отдельных вариантов перестроек гена KMT2A. Так, в нескольких исследованиях, включавших пациентов взрослого и детского возраста, было продемонстрировано, что более благоприятным прогнозом характеризуются ОМЛ с t(1;11)(q21;q23.3)/KMT2A::MLLT1 и t(9;11)(q21;q23.3)/KMT2A::MLLT3. Тем не менее, в других исследованиях данные результаты не были воспроизведены. Кроме того, в ряде исследований было показано, что прогноз выживаемости у пациентов в возрасте от 0 до 24 месяцев с KMT2A-позитивным ОЛ может зависеть не только от природы гена-партнера, но и от локализации точки разрыва в гене KMT2A – при этом наиболее неблагоприятным прогнозом характеризуется разрыв в 11-м интроне. Целью данной работы являлась оценка прогностического значения характера перестройки гена KMT2A при ОМЛ у детей. По нашим данным, природа гена-партнера и локализация точки разрыва не оказывали значимого влияния на результаты терапии пациентов детского возраста с KMT2A-позитивным ОМЛ по протоколу ОМЛ-MRD-2018, что может свидетельствовать о потенциальной целесообразности стратификации этих пациентов в группу высокого риска, вне зависимости от природы гена-партнера и локализации точки разрыва.
Список литературы
1. de Rooij J.D., Zwaan C.M., van den Heuvel-Eibrink M. Pediatric AML: from biology to clinical management. J Clin Med 2015; 4 (1): 127–49.
2. Conneely S., Stevens A. Acute myeloid leukemia in children: emerging paradigms in genetics and new approaches to therapy. Curr Oncol Rep 2021; 23 (2): 1–13.
3. Meyer C., Larghero P., Almeida Lopes B., Burmeister T., Gröger D., Sutton R., et al. The KMT2A recombinome of acute leukemias in 2023. Leukemia 2023; 37 (5): 988–1005.
4. Sorensen P.H., Chen C.S., Smith F.O., Arthur D.C., Domer P.H., Bernstein I.D., et al. Molecular rearrangements of the MLL gene are present in most cases of infant acute myeloid leukemia and are strongly correlated with monocytic or myelomonocytic phenotypes. J Clin Invest 1994; 93 (1): 429–37.
5. Webb D.K., Harrison G., Stevens R.F., Gibson B.G., Hann I.M., Wheatley K. Relationships between age at diagnosis, clinical features , and outcome of therapy in children treated in the Medical Research Council AML 10 and 12 trials for acute myeloid leukemia. Blood 2001; 98 (6): 1714–20.
6. Harrison C.О., Hills R.K., Moorman A.V., Grimwade D.J., Hann I., Webb D.K.H., et al. Cytogenetics of Childhood Acute Myeloid Leukemia: United Kingdom Medical Research Council Treatment Trials AML 10 and 12. J Clin Oncol 2010; 28 (16): 2674–81.
7. Balgobind B.V., Raimondi S.C., Harbott J., Zimmermann M., Alonzo T.A., Auvrignon A., et al. Novel prognostic subgroups in childhood 11q23/ MLL-rearranged acute myeloid leukemia: Results of an international retrospective study. Blood 2009; 114 (12): 2489–96.
8. Coenen E.A., Raimondi S.C., Harbott J., Zimmermann M., Alonzo T.A., Auvrignon A., et al. Prognostic significance of additional cytogenetic aberrations in 733 de novo pediatric 11q23/MLL-rearranged AML patients: results of an international study. Blood 2011; 117 (26): 7102–11.
9. Pollard J.A., Guest E., Alonzo T.A., Gerbing R.B., Loken M.R., Brodersen L.E., et al. Gemtuzumab Ozogamicin improves event-free survival and reduces relapse in pediatric KMT2A-rearranged AML: results from the phase III Children’s Oncology Group trial AAML0531. J Clin Oncol 2021; 39 (28): 3149–60.
10. Dohner H., Wei A.H., Appelbaum F.R., Craddock C., DiNardo C.D., Dombret H., et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 2022; 140 (12): 1345–77.
11. van Weelderen R.E., Harrison C.J., Klein K., Jiang Y., Abrahamsson J., Alonzo T., et al. Optimized cytogenetic risk-group stratification of KMT2A-rearranged pediatric acute myeloid leukemia. Blood Adv 2024; 8 (12): 3200–13.
12. Emerenciano M., Meyer C., Mansur M.B., Marschalek R., Pombo-de-Oliveira M.S. The distribution of MLL breakpoints correlates with outcome in infant acute leukaemia. Br J Haematol 2013; 161 (2): 224– 36.
13. Цаур Г.А., Мейер К., Ригер Т.О., Кустанович А.М., Флейшман Е.В., Ольшанская Ю.В. и др. Острые лейкозы у детей первого года жизни: прогностическое значение локализации точки разрыва в ДНК гена MLL. Клиническая онкогематология 2016; 9 (1): 22–9. DOI: 10.21320/2500-2139-2016-9-1-22-29
14. Jansen M.W., van der Velden V.H., van Dongen J.J. Efficient and easy detection of MLL-AF4, MLL-AF9 and MLL-ENL fusion gene transcripts by multiplex real-time quantitative RT-PCR in TaqMan and LightCycler. Leukemia 2005; 19 (11): 2016–8.
15. Zerkalenkova E., Lebedeva S., Kazakova A., Tsaur G., Starichkova Y., Timofeeva N., et al. Acute myeloid leukemia with t(10;11)(p1112;q23.3): Results of Russian Pediatric AML registration study. Int J Lab Hematol 2019; 41 (2): 287–92.
16. Prasad R., Gu Y., Alder H., Nakamura T., Canaani O., Saito H., et al. Cloning of the ALL-1 fusion partner, the AF-6 gene, involved in acute myeloid leukemias with the t(6;11) chromosome translocation. Cancer Res 1993; 53 (23): 5624–8.
17. Mitani K., Kanda Y., Ogawa S., Tanaka T., Inazawa J., Yazaki Y., Hirai H. Cloning of several species of MLL/MEN chimeric cDNAs in myeloid leukemia with t(11;19)(q23;p13.1) translocation. Blood 1995; 85 (8): 2017–24.
18. Burmeister T., Meyer C., Gröger D.,Hofmann J., Marschalek R. Evidence-based RT-PCR methods for the detection of the 8 most common MLL aberrations in acute leukemias. Leuk Res 2015; 39 (2): 242–7.
19. Suzukawa K., Shimizu S., Nemoto N., Takei N., Taki T., Nagasawa T. Identification of a chromosomal breakpoint and detection of a novel form of an MLL-AF17 fusion transcript in acute monocytic leukemia with t(11;17)(q23;q21). Int J Hematol 2005; 82 (1): 38–41.
20. Uhrig S., Ellermann J., Walther T.,Burkhardt P., Fröhlich M., Hutter B., et al. Accurate and efficient detection of gene fusions from RNA sequencing data. Genome Res 2021; 31 (3): 448–60.
21. Rubnitz J.E., Raimondi S.C., Tong X., Srivastava D.K., Razzouk B.I., Shurtleff S.A., et al. Favorable impact of the t(9;11) in childhood acute myeloid leukemia. J Clin Oncol 2002; 20 (9): 2302–9.
22. Martinez-Climent J.A., Espinosa R. 3rd, Thirman M.J., Le Beau M.M., Rowley J.D. Abnormalities of chromosome band 11q23 and the MLL gene in pediatric myelomonocytic and monoblastic leukemias. Identification of the t(9;11) as an indicator of long survival. J Pediatr Hematol Oncol 1995; 17 (4): 277–83.
Pediatric Hematology/Oncology and Immunopathology. 2025; 24: 58-65
The prognostic significance of partner genes and breakpoint locations in children with KMT2A-rearranged acute myeloid leukemia
https://doi.org/10.24287/1726-1708-2025-24-1-58-65Abstract
Acute myeloid leukemia (AML) with KMT2A rearrangements is one of the most common AML subtypes in children. KMT2A rearrangements are extremely heterogeneous because of different breakpoint locations in the DNA of this gene in combination with a large number of various partner genes. Patients with KMT2A-rearranged AML are typically stratified into a high-risk group. However, there are reports of different prognostic significance of different rearrangements of this gene found both in Russian and international literature. For example, several studies including both adults and children suggested that AML with t(1;11)(q21;q23.3)/KMT2A::MLLT1 and t(9;11)(q21;q23.3)/KMT2A::MLLT3 translocations had a more favorable prognosis. However, these findings failed to be reproduced in other studies. What is more, a number of studies stated that the prognosis of survival in patients aged 0–24 months affected by KMT2A-rearranged acute leukemia may depend not only on the partner gene but also on the location of a breakpoint in the KMT2A gene, while also saying that patients with a breakpoint in intron 11 have the worst prognosis. Here, we aimed to evaluate the prognostic significance of KMT2A rearrangements in children with AML. 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 of Ministry of Healthcare of Russia. We concluded that specific partner gene and breakpoint location did not have any significant influence on treatment outcomes in children with KMT2A-rearranged AML who had been treated according to the AML-MRD-2018 protocol. These findings may indicate that such patients should be stratified into a high-risk group irrespective of the involved partner gene and breakpoint location.
References
1. de Rooij J.D., Zwaan C.M., van den Heuvel-Eibrink M. Pediatric AML: from biology to clinical management. J Clin Med 2015; 4 (1): 127–49.
2. Conneely S., Stevens A. Acute myeloid leukemia in children: emerging paradigms in genetics and new approaches to therapy. Curr Oncol Rep 2021; 23 (2): 1–13.
3. Meyer C., Larghero P., Almeida Lopes B., Burmeister T., Gröger D., Sutton R., et al. The KMT2A recombinome of acute leukemias in 2023. Leukemia 2023; 37 (5): 988–1005.
4. Sorensen P.H., Chen C.S., Smith F.O., Arthur D.C., Domer P.H., Bernstein I.D., et al. Molecular rearrangements of the MLL gene are present in most cases of infant acute myeloid leukemia and are strongly correlated with monocytic or myelomonocytic phenotypes. J Clin Invest 1994; 93 (1): 429–37.
5. Webb D.K., Harrison G., Stevens R.F., Gibson B.G., Hann I.M., Wheatley K. Relationships between age at diagnosis, clinical features , and outcome of therapy in children treated in the Medical Research Council AML 10 and 12 trials for acute myeloid leukemia. Blood 2001; 98 (6): 1714–20.
6. Harrison C.O., Hills R.K., Moorman A.V., Grimwade D.J., Hann I., Webb D.K.H., et al. Cytogenetics of Childhood Acute Myeloid Leukemia: United Kingdom Medical Research Council Treatment Trials AML 10 and 12. J Clin Oncol 2010; 28 (16): 2674–81.
7. Balgobind B.V., Raimondi S.C., Harbott J., Zimmermann M., Alonzo T.A., Auvrignon A., et al. Novel prognostic subgroups in childhood 11q23/ MLL-rearranged acute myeloid leukemia: Results of an international retrospective study. Blood 2009; 114 (12): 2489–96.
8. Coenen E.A., Raimondi S.C., Harbott J., Zimmermann M., Alonzo T.A., Auvrignon A., et al. Prognostic significance of additional cytogenetic aberrations in 733 de novo pediatric 11q23/MLL-rearranged AML patients: results of an international study. Blood 2011; 117 (26): 7102–11.
9. Pollard J.A., Guest E., Alonzo T.A., Gerbing R.B., Loken M.R., Brodersen L.E., et al. Gemtuzumab Ozogamicin improves event-free survival and reduces relapse in pediatric KMT2A-rearranged AML: results from the phase III Children’s Oncology Group trial AAML0531. J Clin Oncol 2021; 39 (28): 3149–60.
10. Dohner H., Wei A.H., Appelbaum F.R., Craddock C., DiNardo C.D., Dombret H., et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 2022; 140 (12): 1345–77.
11. van Weelderen R.E., Harrison C.J., Klein K., Jiang Y., Abrahamsson J., Alonzo T., et al. Optimized cytogenetic risk-group stratification of KMT2A-rearranged pediatric acute myeloid leukemia. Blood Adv 2024; 8 (12): 3200–13.
12. Emerenciano M., Meyer C., Mansur M.B., Marschalek R., Pombo-de-Oliveira M.S. The distribution of MLL breakpoints correlates with outcome in infant acute leukaemia. Br J Haematol 2013; 161 (2): 224– 36.
13. Tsaur G.A., Meier K., Riger T.O., Kustanovich A.M., Fleishman E.V., Ol'shanskaya Yu.V. i dr. Ostrye leikozy u detei pervogo goda zhizni: prognosticheskoe znachenie lokalizatsii tochki razryva v DNK gena MLL. Klinicheskaya onkogematologiya 2016; 9 (1): 22–9. DOI: 10.21320/2500-2139-2016-9-1-22-29
14. Jansen M.W., van der Velden V.H., van Dongen J.J. Efficient and easy detection of MLL-AF4, MLL-AF9 and MLL-ENL fusion gene transcripts by multiplex real-time quantitative RT-PCR in TaqMan and LightCycler. Leukemia 2005; 19 (11): 2016–8.
15. Zerkalenkova E., Lebedeva S., Kazakova A., Tsaur G., Starichkova Y., Timofeeva N., et al. Acute myeloid leukemia with t(10;11)(p1112;q23.3): Results of Russian Pediatric AML registration study. Int J Lab Hematol 2019; 41 (2): 287–92.
16. Prasad R., Gu Y., Alder H., Nakamura T., Canaani O., Saito H., et al. Cloning of the ALL-1 fusion partner, the AF-6 gene, involved in acute myeloid leukemias with the t(6;11) chromosome translocation. Cancer Res 1993; 53 (23): 5624–8.
17. Mitani K., Kanda Y., Ogawa S., Tanaka T., Inazawa J., Yazaki Y., Hirai H. Cloning of several species of MLL/MEN chimeric cDNAs in myeloid leukemia with t(11;19)(q23;p13.1) translocation. Blood 1995; 85 (8): 2017–24.
18. Burmeister T., Meyer C., Gröger D.,Hofmann J., Marschalek R. Evidence-based RT-PCR methods for the detection of the 8 most common MLL aberrations in acute leukemias. Leuk Res 2015; 39 (2): 242–7.
19. Suzukawa K., Shimizu S., Nemoto N., Takei N., Taki T., Nagasawa T. Identification of a chromosomal breakpoint and detection of a novel form of an MLL-AF17 fusion transcript in acute monocytic leukemia with t(11;17)(q23;q21). Int J Hematol 2005; 82 (1): 38–41.
20. Uhrig S., Ellermann J., Walther T.,Burkhardt P., Fröhlich M., Hutter B., et al. Accurate and efficient detection of gene fusions from RNA sequencing data. Genome Res 2021; 31 (3): 448–60.
21. Rubnitz J.E., Raimondi S.C., Tong X., Srivastava D.K., Razzouk B.I., Shurtleff S.A., et al. Favorable impact of the t(9;11) in childhood acute myeloid leukemia. J Clin Oncol 2002; 20 (9): 2302–9.
22. Martinez-Climent J.A., Espinosa R. 3rd, Thirman M.J., Le Beau M.M., Rowley J.D. Abnormalities of chromosome band 11q23 and the MLL gene in pediatric myelomonocytic and monoblastic leukemias. Identification of the t(9;11) as an indicator of long survival. J Pediatr Hematol Oncol 1995; 17 (4): 277–83.
