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Comprehensive molecular understanding of pediatric acute myeloid leukemia

  • Progress in Hematology
  • Recent progress in pediatric leukemia
  • Published:
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Abstract

Pediatric acute myeloid leukemia (AML) is a heterogeneous disease with various genetic abnormalities. Recent advances in genetic analysis have enabled the identification of causative genes in > 90% of pediatric AML cases. Fusion genes such as RUNX1::RUNX1T1, CBFB::MYH11, and KMT2A::MLLT3 are frequently detected in > 70% of pediatric AML cases, whereas FLT3-internal tandem duplication, CEBPA-bZip, and NPM1 mutations are detected in approximately 5–15% of cases, respectively. Conversely, mutations in DNMT3A, TET2, and IDH, which are common in adults, are extremely rare in pediatric AML. The genetic characteristics of pediatric AML are slightly different from those of adult AML. For accurate risk stratification and treatment intensity, genome analysis should be performed in a simple, fast, and inexpensive manner and the results should be returned to patients in real time. As with acute lymphoblastic leukemia, the presence or absence of minimal residual disease is an important factor in determining the success of treatment against AML, and it is important to predict prognosis and formulate treatment strategies considering the genetic abnormalities. For the development and clinical application of new molecularly targeted therapies based on identified genetic abnormalities, it is necessary to explore when and in which combinations drugs will be most effective.

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References

  1. Takahashi H, Watanabe T, Kinoshita A, Yuza Y, Moritake H, Terui K, et al. High event-free survival rate with minimum-dose-anthracycline treatment in childhood acute promyelocytic leukaemia: a nationwide prospective study by the Japanese paediatric leukaemia/lymphoma study group. Br J Haematol. 2016;174(3):437–43. https://doi.org/10.1111/bjh.14068.

    Article  CAS  Google Scholar 

  2. Taga T, Watanabe T, Tomizawa D, Kudo K, Terui K, Moritake H, et al. Preserved high probability of overall survival with significant reduction of chemotherapy for myeloid leukemia in down syndrome: a nationwide prospective study in Japan. Pediatr Blood Cancer. 2016;63(2):248–54. https://doi.org/10.1002/pbc.25789.

    Article  CAS  Google Scholar 

  3. Fröhling S, Scholl C, Gilliland DG, Levine RL. Genetics of myeloid malignancies: pathogenetic and clinical implications. J Clin Oncol. 2005;23(26):6285–95. https://doi.org/10.1200/JCO.2005.05.010.

    Article  CAS  Google Scholar 

  4. Marcucci G, Haferlach T, Döhner H. Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol. 2011;29(5):475–86. https://doi.org/10.1200/JCO.2010.30.2554.

    Article  CAS  Google Scholar 

  5. Fröhling S, Schlenk RF, Stolze I, Bihlmayr J, Benner A, Kreitmeier S, et al. CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. J Clin Oncol. 2004;22(4):624–33. https://doi.org/10.1200/JCO.2004.06.060.

    Article  CAS  Google Scholar 

  6. Shimada A, Taki T, Tabuchi K, Tawa A, Horibe K, Tsuchida M, et al. KIT mutations, and not FLT3 internal tandem duplication, are strongly associated with a poor prognosis in pediatric acute myeloid leukemia with t(8;21): a study of the Japanese childhood AML cooperative study group. Blood. 2006;107(5):1806–9. https://doi.org/10.1182/blood-2005-08-3408.

    Article  CAS  Google Scholar 

  7. Abbas S, Lugthart S, Kavelaars FG, Schelen A, Koenders JE, Zeilemaker A, et al. Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value. Blood. 2010;116(12):2122–6. https://doi.org/10.1182/blood-2009-11-250878.

    Article  CAS  Google Scholar 

  8. Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson A, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059–74. https://doi.org/10.1056/NEJMoa1301689.

    Article  CAS  Google Scholar 

  9. Shiba N, Yoshida K, Shiraishi Y, Okuno Y, Yamato G, Hara Y, et al. Whole-exome sequencing reveals the spectrum of gene mutations and the clonal evolution patterns in paediatric acute myeloid leukaemia. Br J Haematol. 2016;175(3):476–89. https://doi.org/10.1111/bjh.14247.

    Article  CAS  Google Scholar 

  10. Gruber TA, Larson Gedman A, Zhang J, Koss CS, Marada S, Ta HQ, et al. An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia. Cancer Cell. 2012;22(5):683–97. https://doi.org/10.1016/j.ccr.2012.10.007.

    Article  CAS  Google Scholar 

  11. Thiollier C, Lopez CK, Gerby B, Ignacimouttou C, Poglio S, Duffourd Y, et al. Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models. J Exp Med. 2012;209(11):2017–31. https://doi.org/10.1084/jem.20121343.

    Article  CAS  Google Scholar 

  12. de Rooij JD, Hollink IH, Arentsen-Peters ST, van Galen JF, Berna Beverloo H, Baruchel A, et al. NUP98/JARID1A is a novel recurrent abnormality in pediatric acute megakaryoblastic leukemia with a distinct HOX gene expression pattern. Leukemia. 2013;27(12):2280–8. https://doi.org/10.1038/leu.2013.87.

    Article  CAS  Google Scholar 

  13. Hara Y, Shiba N, Ohki K, Tabuchi K, Yamato G, Park MJ, 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. https://doi.org/10.1002/gcc.22444.

    Article  CAS  Google Scholar 

  14. de Rooij JD, Branstetter C, Ma J, Li Y, Walsh MP, Cheng J, Gruber TA, 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. https://doi.org/10.1038/ng.3772.

    Article  CAS  Google Scholar 

  15. Yamato G, Kawai T, Shiba N, Ikeda J, Hara Y, Ohki KT, et al. Genome-wide DNA methylation analysis in pediatric acute myeloid leukemia. Blood Adv. 2022;6(11):3207–19. https://doi.org/10.1182/bloodadvances.2021005381.

    Article  CAS  Google Scholar 

  16. Inaba H, Coustan-Smith E, Cao X, Pounds SB, Shurtleff SA, Wang KY, et al. Comparative analysis of different approaches to measure treatment response in acute myeloid leukemia. J Clin Oncol. 2012;30(29):3625–32. https://doi.org/10.1200/JCO.2011.41.5323.

    Article  Google Scholar 

  17. Rubnitz JE, Inaba H, Dahl G, Ribeiro RC, Bowman WP, Taub J, et al. Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial. Lancet Oncol. 2010;11(6):543–52. https://doi.org/10.1016/S1470-2045(10)70090-5.

    Article  CAS  Google Scholar 

  18. Loken MR, Alonzo TA, Pardo L, Gerbing RB, Raimondi SC, Hirsch BA, et al. Residual disease detected by multidimensional flow cytometry signifies high relapse risk in patients with de novo acute myeloid leukemia: a report from children’s oncology group. Blood. 2012;120(8):1581–8. https://doi.org/10.1182/blood-2012-02-408336.

    Article  Google Scholar 

  19. Tomizawa D, Tsujimoto S, Tanaka S, Matsubayashi J, Aoki T, Iwamoto S, et al. A phase III clinical trial evaluating efficacy and safety of minimal residual disease-based risk stratification for children with acute myeloid leukemia, incorporating a randomized study of gemtuzumab ozogamicin in combination with post-induction chemotherapy for non-low-risk patients (JPLSG-AML-20). Jpn J Clin Oncol. 2022;52(10):1225–31. https://doi.org/10.1093/jjco/hyac105.

    Article  Google Scholar 

  20. Tokumasu M, Murata C, Shimada A, Ohki K, Hayashi Y, Saito AM, et al. Adverse prognostic impact of KIT mutations in childhood CBF-AML: the results of the Japanese pediatric leukemia/lymphoma study group AML-05 trial. Leukemia. 2015;29(12):2438–41. https://doi.org/10.1038/leu.2015.121.

    Article  CAS  Google Scholar 

  21. Faber ZJ, Chen X, Gedman AL, Boggs K, Cheng J, Ma J, et al. The genomic landscape of core-binding factor acute myeloid leukemias. Nat Genet. 2016;48(12):1551–6. https://doi.org/10.1038/ng.3709.

    Article  CAS  Google Scholar 

  22. Hara Y, Shiba N, Yamato G, Ohki K, Tabuchi K, Sotomatsu M, et al. Patients aged less than 3 years with acute myeloid leukaemia characterize a molecularly and clinically distinct subgroup. Br J Haematol. 2020;188(4):528–39. https://doi.org/10.1111/bjh.16203.

    Article  CAS  Google Scholar 

  23. Jo A, Mitani S, Shiba N, Hayashi Y, Hara Y, Takahashi H, et al. High expression of EVI1 and MEL1 is a compelling poor prognostic marker of pediatric AML. Leukemia. 2015;29(5):1076–83. https://doi.org/10.1038/leu.2015.5.

    Article  CAS  Google Scholar 

  24. Matsuo H, Kajihara M, Tomizawa D, Watanabe T, Saito AM, Fujimoto J, et al. EVI1 overexpression is a poor prognostic factor in pediatric patients with mixed lineage leukemia-AF9 rearranged acute myeloid leukemia. Haematologica. 2014;99(11):e225–7. https://doi.org/10.3324/haematol.2014.107128.

    Article  CAS  Google Scholar 

  25. Shiba N, Ichikawa H, Taki T, Park MJ, Jo A, Mitani S, et al. NUP98-NSD1 gene fusion and its related gene expression signature are strongly associated with a poor prognosis in pediatric acute myeloid leukemia. Genes Chromosom Cancer. 2013;52(7):683–93. https://doi.org/10.1002/gcc.22064.

    Article  CAS  Google Scholar 

  26. Umeda M, Ma J, Huang BJ, Hagiwara K, Westover T, Abdelhamed S, et al. Integrated genomic analysis identifies UBTF tandem duplications as a recurrent lesion in pediatric acute myeloid leukemia. Blood Cancer Discov. 2022;3(3):194–207. https://doi.org/10.1158/2643-3230.BCD-21-0160.

    Article  CAS  Google Scholar 

  27. O’Hear C, Inaba H, Pounds S, Shi L, Dahl G, Bowman WP, et al. Gemtuzumab ozogamicin can reduce minimal residual disease in patients with childhood acute myeloid leukemia. Cancer. 2013;119(22):4036–43. https://doi.org/10.1002/cncr.28334.

    Article  CAS  Google Scholar 

  28. Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC, et al. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III children’s oncology group trial AAML0531. J Clin Oncol. 2014;32(27):3021–32. https://doi.org/10.1200/JCO.2014.55.3628.

    Article  CAS  Google Scholar 

  29. Niktoreh N, Lerius B, Zimmermann M, Gruhn B, Escherich G, Bourquin JP, et al. Gemtuzumab ozogamicin in children with relapsed or refractory acute myeloid leukemia: a report by Berlin-Frankfurt-Münster study group. Haematologica. 2019;104(1):120–7. https://doi.org/10.3324/haematol.2018.191841.

    Article  CAS  Google Scholar 

  30. Rubnitz JE, Kaspers GJL. How i treat pediatric acute myeloid leukemia. Blood. 2021;138(12):1009–18. https://doi.org/10.1182/blood.2021011694.

    Article  CAS  Google Scholar 

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Acknowledgements

I am grateful to Drs. Yasuhide Hayashi and Seishi Ogawa for their passionate guidance. I also gratefully acknowledge the work of past and present colleagues of the laboratory. The author would like to thank Enago (www.enago.jp) for the English language review.

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  1. Department of Pediatrics, Yokohama City University Graduate School of Medicine, 3-9, Fukuura, Kanazawa-Ku, Yokohama, 236-0004, Japan

    Norio Shiba

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Shiba, N. Comprehensive molecular understanding of pediatric acute myeloid leukemia. Int J Hematol 117, 173–181 (2023). https://doi.org/10.1007/s12185-023-03533-x

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  • DOI: https://doi.org/10.1007/s12185-023-03533-x

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