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Extensive mutational status of genes and clinical outcome in pediatric acute myeloid leukemia

Leukemia volume 24, pages 205–209 (2010)Cite this article

Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous but aggressive disease in which cytogenetic findings are considered to be the most powerful single prognostic factor.1 Most patients belong to the category with standard-risk disease and the stratification of this heterogeneous group seems to be insufficient. Along with cytogenetics, mutational analysis is one of the most important approaches to gain understanding of the molecular bases of leukemogenesis. Dash and Gilliland2 suggested that AML blasts develop from normal blasts affected by two types of genetic damage: class I and class II mutations. Class I mutations result in constitutive activation of cell surface receptors and confer a proliferative and survival advantage on the blast cells. This group includes activating mutations in receptor tyrosine kinases such as FLT3 (fms-like tyrosine kinase-3) and c-KIT and in the GTPase RAS family. In contrast, class II mutations seem to impair differentiation, but are not sufficient to cause leukemia when expressed alone. This second group includes chromosomal rearrangements leading to AML1-ETO, CBFβ-MYH11 or MLL fusion genes, deregulation of HOX genes expression and mutations in CEBPα (CCAAT/enhancer-binding protein α) gene. More recently, gene mutations in two new molecular markers, NPM1 (nucleophosmin) and WT1 (Wilms'mor 1), were reported to have a critical function in leukemia. The two-hit model of leukemogenesis, combining an activating lesion of tyrosine kinase pathways with event-blocking myeloid differentiation, seems very interesting to screen molecular events in AML patients, in view of the frequent association of a class I and a class II mutation.

There exist many studies of the frequency and prognostic significance of gene mutations in adult AML. Very few studies have been performed in pediatric populations. We studied a well-characterized cohort of 76 children with de novo AML and evaluated at diagnosis the frequency and the impact on clinical outcome of FLT3 internal tandem duplication (FLT3-ITD) and tyrosine kinase domain (FLT3-TKD), c-KIT, N-RAS, K-RAS, CEBPα, NPM1 and WT1 gene mutations in pediatric AML with a long clinical follow-up (median, 72 months). The main aim of the study was to determine whether these molecular lesions could be used to improve the molecular-risk stratification to better predict the response to therapy.

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References

  1. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 1998; 92: 2322–2333.

    CAS  Google Scholar 

  2. Dash A, Gilliland DG . Molecular genetics of acute myeloid leukaemia. Best Pract Res Clin Haematol 2001; 14: 49–64.

    Article  CAS  Google Scholar 

  3. Zwaan CM, Meshinchi S, Radich JP, Veerman AJ, Huismans DR, Munske L et al. FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance. Blood 2003; 102: 2387–2394.

    Article  CAS  Google Scholar 

  4. Brown P, McIntyre E, Rau R, Meshinchi S, Lacayo N, Dahl G et al. The incidence and clinical significance of nucleophosmin mutations in childhood AML. Blood 2007; 110: 979–985.

    Article  CAS  Google Scholar 

  5. Goemans BF, Zwaan CM, Miller M, Zimmermann M, Harlow A, Meshinchi S et al. Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia. Leukemia 2005; 19: 1536–1542.

    Article  CAS  Google Scholar 

  6. Ho PA, Alonzo TA, Gerbing RB, Pollard J, Stirewalt DL, Hurwitz C et al. Prevalence and prognostic implications of CEBPA mutations in pediatric AML: a report from the Children's Oncology Group. Blood 2009; 113: 6558–6566.

    Article  CAS  Google Scholar 

  7. Paschka P, Marcucci G, Ruppert AS, Whitman SP, Mrozek K, Maharry K et al. Wilms'mor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol 2008; 26: 4595–4602.

    Article  CAS  Google Scholar 

  8. Virappane P, Gale R, Hills R, Kakkas I, Summers K, Stevens J et al. Mutation of the Wilms'mor 1 gene is a poor prognostic factor associated with chemotherapy resistance in normal karyotype acute myeloid leukemia: the United Kingdom Medical Research Council Adult Leukaemia Working Party. J Clin Oncol 2008; 26: 5429–5435.

    Article  CAS  Google Scholar 

  9. Hollink IH, van den Heuvel-Eibrink MM, Zimmermann M, Balgobind BV, Arentsen-Peters ST, Alders M et al. Clinical relevance of Wilms'mor 1 gene mutations in childhood acute myeloid leukemia. Blood 2009; 113: 5951–5960.

    Article  CAS  Google Scholar 

  10. Preudhomme C, Sagot C, Boissel N, Cayuela JM, Tigaud I, de Botton S et al. Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). Blood 2002; 100: 2717–2723.

    Article  CAS  Google Scholar 

  11. 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: 1806–1809.

    Article  CAS  Google Scholar 

  12. Cilloni D, Gottardi E, De Micheli D, Serra A, Volpe G, Messa F et al. Quantitative assessment of WT1 expression by real time quantitative PCR may be a useful tool for monitoring minimal residual disease in acute leukemia patients. Leukemia 2002; 16: 2115–2121.

    Article  CAS  Google Scholar 

  13. Lapillonne H, Renneville A, Auvrignon A, Flamant C, Blaise A, Perot C et al. High WT1 expression after induction therapy predicts high risk of relapse and death in pediatric acute myeloid leukemia. J Clin Oncol 2006; 24: 1507–1515.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by the Association pour la recherche dans les maladies hématologiques de l'ant (ARMHE), the Association Laurette Fugain, fondation de France (comité leucémie) and northwest canceropole (axis 2). We thank all the technicians of the laboratories involved for their excellent contribution to this work.

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Authors and Affiliations

  1. INSERM, UMR_S 938, Proliferation and Differentiation of Stem Cells, Paris, France

    H Lapillonne, A Auvrignon, M Labopin, L Douay, G Leverger & J Landman-Parker

  2. UPMC University of Paris 06, UMR_S938, Proliferation and Differentiation of Stem Cells, Paris, France

    H Lapillonne, L Douay, G Leverger & J Landman-Parker

  3. Department of Hematology, AP-HP, Biology and Pathology, Armand Trousseau Hospital, Paris, France

    H Lapillonne, P Ballerini, M Adam & L Douay

  4. Univ Lille Nord de France and Laboratoire d'acute;matologie, CHU de Lille, and Inserm U837 and North-west Canceropole, Lille, France

    L Llopis, A Renneville, F Mazingue, J-L Lai, N Philippe, V Zurawski & C Preudhomme

  5. Department of Pediatric Hematology/Oncology, AP-HP, Armand Trousseau Hospital, Paris, France

    A Auvrignon, G Leverger & J Landman-Parker

  6. AP-HP, Saint-Antoine Hospital, CEREST-TC, Paris, France

    M Labopin

  7. Department of Hematology, AP-HP, Biology and Cytogenetic, Saint-Antoine Hospital, Paris, France

    C Perot

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  1. H Lapillonne
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  16. C Preudhomme
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Correspondence to C Preudhomme.

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Lapillonne, H., Llopis, L., Auvrignon, A. et al. Extensive mutational status of genes and clinical outcome in pediatric acute myeloid leukemia. Leukemia 24, 205–209 (2010). https://doi.org/10.1038/leu.2009.172

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