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Acute Non Lymphocytic Leukemia

Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia

Leukemia volume 19, pages 1536–1542 (2005)Cite this article

Abstract

Activating mutations in RAS and receptor tyrosine kinases such as KIT and FLT3 are hypothesized to cooperate with chimeric transcription factors in the pathogenesis of acute myeloid leukemia (AML). To test this hypothesis, we genotyped 150 pediatric AML samples for mutations in KIT (exons 8, 17), NRAS and KRAS (exons 1, 2) and FLT3/ITD. This is the largest cohort of pediatric AML patients reported thus far screened for all four mutations. Of the children with AML, 40% had a mutation in KIT (11.3%), RAS (18%) or FLT3/ITD (11.1%), and 70% of cases of core-binding factor (CBF) leukemia were associated with a mutation of KIT or RAS. Mutations in RAS or FLT3/ITD were frequently found in association with a normal karyotype. Patients with a FLT3/ITD mutation had a significantly worse clinical outcome. However, the presence of a KIT or RAS mutation did not significantly influence clinical outcome. We demonstrate that KIT exon 8 mutations result in constitutive ligand-independent kinase activation that can be inhibited by clinically relevant concentrations of imatinib. Our results demonstrate that abnormalities of signal transduction pathways are frequent in pediatric AML. Future clinical studies are needed to determine whether selective targeting of these abnormalities will improve treatment results.

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References

  1. Creutzig U, Ritter J, Zimmermann M, Hermann J, Gadner H, Sawatzki DB et al. Idarubicin improves blast cell clearance during induction therapy in children with AML: results of study AML-BFM 93. AML-BFM Study Group. Leukemia 2001; 15: 348–354.

    Article  CAS  PubMed  Google Scholar 

  2. Woods WG, Neudorf S, Gold S, Sanders J, Buckley JD, Barnard DR et al. A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission. Blood 2001; 97: 56–62.

    Article  CAS  PubMed  Google Scholar 

  3. Hann IM, Webb DK, Gibson BE, Harrison CJ . MRC trials in childhood acute myeloid leukaemia. Ann Hematol 2004; 83 (Suppl. 1): S108–S112.

    PubMed  Google Scholar 

  4. Perel Y, Auvrignon A, Leblanc T, Vannier JP, Michel G, Nelken B et al. Impact of addition of maintenance therapy to intensive induction and consolidation chemotherapy for childhood acute myeloblastic leukemia: results of a prospective randomized trial, LAME 89/91. Leucamie Aique Myeloide Enfant. J Clin Oncol 2002; 20: 2774–2782.

    Article  PubMed  Google Scholar 

  5. 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 1612 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  PubMed  Google Scholar 

  6. Yuan Y, Zhou L, Miyamoto T, Iwasaki H, Harakawa N, Hetherington CJ et al. AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proc Natl Acad Sci USA 2001; 98: 10398–10403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kelly LM, Kutok JL, Williams IR, Boulton CL, Amaral SM, Curley DP et al. PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. Proc Natl Acad Sci USA 2002; 99: 8283–8288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Grisolano JL, O'Neal J, Cain J, Tomasson MH . An activated receptor tyrosine kinase, TEL/PDGFbetaR, cooperates with AML1/ETO to induce acute myeloid leukemia in mice. Proc Natl Acad Sci USA 2003; 100: 9506–9511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Castilla LH, Garrett L, Adya N, Orlic D, Dutra A, Anderson S et al. The fusion gene Cbfb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia. Nat Genet 1999; 23: 144–146.

    Article  CAS  PubMed  Google Scholar 

  10. Hart SM, Foroni L . Core binding factor genes and human leukemia. Haematologica 2002; 87: 1307–1323.

    CAS  PubMed  Google Scholar 

  11. Kitayama H, Tsujimura T, Matsumura I, Oritani K, Ikeda H, Ishikawa J et al. Neoplastic transformation of normal hematopoietic cells by constitutively activating mutations of c-kit receptor tyrosine kinase. Blood 1996; 88: 995–1004.

    CAS  PubMed  Google Scholar 

  12. Janssen JW, Steenvoorden AC, Collard JG, Nusse R . Oncogene activation in human myeloid leukemia. Cancer Res 1985; 45: 3262–3267.

    CAS  PubMed  Google Scholar 

  13. Hayakawa F, Towatari M, Kiyoi H, Tanimoto M, Kitamura T, Saito H et al. Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene 2000; 19: 624–631.

    Article  CAS  PubMed  Google Scholar 

  14. Chan IT, Gilliland DG . Oncogenic K-ras in mouse models of myeloproliferative disease and acute myeloid leukemia. Cell Cycle 2004; 3: 536–537.

    Article  CAS  PubMed  Google Scholar 

  15. Heinrich MC, Blanke CD, Druker BJ, Corless CL . Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol 2002; 20: 1692–1703.

    Article  CAS  PubMed  Google Scholar 

  16. Furitsu T, Tsujimura T, Tono T, Ikeda H, Kitayama H, Koshimizu U et al. Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J Clin Invest 1993; 92: 1736–1744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gari M, Goodeve A, Wilson G, Winship P, Langabeer S, Linch D et al. c-kit proto-oncogene exon 8 in-frame deletion plus insertion mutations in acute myeloid leukaemia. Br J Haematol 1999; 105: 894–900.

    Article  CAS  PubMed  Google Scholar 

  18. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998; 279: 577–580.

    Article  CAS  PubMed  Google Scholar 

  19. Kemmer K, Corless CL, Fletcher JA, McGreevey L, Haley A, Griffith D et al. KIT mutations are common in testicular seminomas. Am J Pathol 2004; 164: 305–313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bos JL . ras oncogenes in human cancer: a review. Cancer Res 1989; 49: 4682–4689.

    CAS  PubMed  Google Scholar 

  21. Radich JP, Kopecky KJ, Willman CL, Weick J, Head D, Appelbaum F et al. N-ras mutations in adult de novo acute myelogenous leukemia: prevalence and clinical significance. Blood 1990; 76: 801–807.

    CAS  PubMed  Google Scholar 

  22. Neubauer A, Dodge RK, George SL, Davey FR, Silver RT, Schiffer CA et al. Prognostic importance of mutations in the ras proto-oncogenes in de novo acute myeloid leukemia. Blood 1994; 83: 1603–1611.

    CAS  PubMed  Google Scholar 

  23. Wang YY, Zhou GB, Yin T, Chen B, Shi JY, Liang WX et al. AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: implication in stepwise leukemogenesis and response to Gleevec. Proc Natl Acad Sci USA 2005; 102: 1104–1109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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  PubMed  Google Scholar 

  25. Creutzig U, Zimmermann M, Ritter J, Henze G, Graf N, Loffler H et al. Definition of a standard-risk group in children with AML. Br J Haematol 1999; 104: 630–639.

    Article  CAS  PubMed  Google Scholar 

  26. Creutzig U, Harbott J, Sperling C, Ritter J, Zimmermann M, Loffler H et al. Clinical significance of surface antigen expression in children with acute myeloid leukemia: results of study AML-BFM-87. Blood 1995; 86: 3097–3108.

    CAS  PubMed  Google Scholar 

  27. Slats AM, Egeler RM, van der Does-van den Berg A, Korbijn C, Hahlen K, Kamps WA et al. Causes of death – other than progressive leukemia – in childhood acute lymphoblastic (ALL) and myeloid leukemia (AML): the Dutch Childhood Oncology Group experience. Leukemia 2005; 19: 537–544.

    Article  CAS  PubMed  Google Scholar 

  28. Corless CL, McGreevey L, Haley A, Town A, Heinrich MC . KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. Am J Pathol 2002; 160: 1567–1572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cruz III F, Rubin BP, Wilson D, Town A, Schroeder A, Haley A et al. Absence of BRAF and NRAS mutations in uveal melanoma. Cancer Res 2003; 63: 5761–5766.

    CAS  PubMed  Google Scholar 

  30. Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003; 21: 4342–4349.

    Article  CAS  PubMed  Google Scholar 

  31. Cheson BD, Cassileth PA, Head DR, Schiffer CA, Bennett JM, Bloomfield CD et al. Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 1990; 8: 813–819.

    Article  CAS  PubMed  Google Scholar 

  32. Beghini A, Peterlongo P, Ripamonti CB, Larizza L, Cairoli R, Morra E et al. C-kit mutations in core binding factor leukemias. Blood 2000; 95: 726–727.

    CAS  PubMed  Google Scholar 

  33. Care RS, Valk PJ, Goodeve AC, Abu-Duhier FM, Geertsma-Kleinekoort WM, Wilson GA et al. Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias. Br J Haematol 2003; 121: 775–777.

    Article  CAS  PubMed  Google Scholar 

  34. Ning ZQ, Li J, Arceci RJ . Activating mutations of c-kit at codon 816 confer drug resistance in human leukemia cells. Leuk Lymphoma 2001; 41: 513–522.

    Article  CAS  PubMed  Google Scholar 

  35. Meshinchi S, Stirewalt DL, Alonzo TA, Zhang Q, Sweetser DA, Woods WG et al. Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia. Blood 2003; 102: 1474–1479.

    Article  CAS  PubMed  Google Scholar 

  36. Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 1999; 93: 3074–3080.

    CAS  PubMed  Google Scholar 

  37. Nakagawa T, Saitoh S, Imoto S, Itoh M, Tsutsumi M, Hikiji K et al. Multiple point mutation of N-ras and K-ras oncogenes in myelodysplastic syndrome and acute myelogenous leukemia. Oncology 1992; 49: 114–122.

    Article  CAS  PubMed  Google Scholar 

  38. Mahgoub N, Parker RI, Hosler MR, Close P, Winick NJ, Masterson M et al. RAS mutations in pediatric leukemias with MLL gene rearrangements. Genes Chromosomes Cancer 1998; 21: 270–275.

    Article  CAS  PubMed  Google Scholar 

  39. Farr C, Gill R, Katz F, Gibbons B, Marshall CJ . Analysis of ras gene mutations in childhood myeloid leukaemia. Br J Haematol 1991; 77: 323–327.

    Article  CAS  PubMed  Google Scholar 

  40. Vogelstein B, Civin CI, Preisinger AC, Krischer JP, Steuber P, Ravindranath Y et al. RAS gene mutations in childhood acute myeloid leukemia: a Pediatric Oncology Group study. Genes Chromosomes Cancer 1990; 2: 159–162.

    Article  CAS  PubMed  Google Scholar 

  41. Lubbert M, Mirro Jr J, Kitchingman G, McCormick F, Mertelsmann R, Herrmann F et al. Prevalence of N-ras mutations in children with myelodysplastic syndromes and acute myeloid leukemia. Oncogene 1992; 7: 263–268.

    CAS  PubMed  Google Scholar 

  42. Sheng XM, Kawamura M, Ohnishi H, Ida K, Hanada R, Kojima S et al. Mutations of the RAS genes in childhood acute myeloid leukemia, myelodysplastic syndrome and juvenile chronic myelocytic leukemia. Leuk Res 1997; 21: 697–701.

    Article  CAS  PubMed  Google Scholar 

  43. Gilliland DG, Griffin JD . Role of FLT3 in leukemia. Curr Opin Hematol 2002; 9: 274–281.

    Article  PubMed  Google Scholar 

  44. Cairoli R, Grillo G, Beghini A, Tedeschi A, Ripamonti CB, Larizza L et al. C-Kit point mutations in core binding factor leukemias: correlation with white blood cell count and the white blood cell index. Leukemia 2003; 17: 471–472.

    Article  CAS  PubMed  Google Scholar 

  45. Beghini A, Cairoli R, Morra E, Larizza L . In vivo differentiation of mast cells from acute myeloid leukemia blasts carrying a novel activating ligand-independent C-kit mutation. Blood Cells Mol Dis 1998; 24: 262–270.

    Article  CAS  PubMed  Google Scholar 

  46. Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ . Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 2000; 96: 925–932.

    CAS  PubMed  Google Scholar 

  47. Growney JD, Clark JJ, Adelsperger J, Stone R, Fabbro D, Griffin JD et al. Activation mutations of human c-KIT resistant to imatinib are sensitive to the tyrosine kinase inhibitor PKC412. Blood 2005, Mar 24 [E-pub ahead of print].

  48. Kohl TM, Schnittger S, Ellwart JW, Hiddemann W, Spiekermann K . KIT exon 8 mutations associated with core-binding factor (CBF)-acute myeloid leukemia (AML) cause hyperactivation of the receptor in response to stem cell factor. Blood 2005; 105: 3319–3321.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank all the hospitals and clinicis participating in the AML-BFM Study Group and the Dutch Childhood Oncology Group, as well as their reference laboratories that provided us with the patient samples and the clinical and cell-biological data. The technicians of the research laboratory of Pediatric Oncology of the VU university medical center handled all samples. This study was financially supported by an unrestricted grant from Novartis Pharma BV, Arnhem, the Netherlands. Additional funding was provided by a Veterans Affairs Grant (MCH) and funding from the Doris Duke Charitable Foundation (MCH) (both unrestricted grants).

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Authors and Affiliations

  1. Department of Pediatric Hematology/Oncology, VU University Medical Center, Amsterdam, The Netherlands

    B F Goemans, Ch M Zwaan, A H Loonen & G J L Kaspers

  2. Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health Sciences University Cancer Institute and Portland VA Medical Center, Portland, OR, USA

    M Miller, A Harlow & M C Heinrich

  3. Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany

    M Zimmermann

  4. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    S Meshinchi

  5. Dutch Childhood Oncology Group, The Hague, The Netherlands

    K Hählen

  6. AML-BFM Study Group, Münster, Germany

    D Reinhardt & U Creutzig

  7. Department of Pediatric Hematology/Oncology, Sophia Children's Hospital, Erasmus Medical Center, Rotterdam, The Netherlands

    Ch M Zwaan & K Hählen

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  1. B F Goemans
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Correspondence to B F Goemans.

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Goemans, B., Zwaan, C., Miller, M. et al. Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia. Leukemia 19, 1536–1542 (2005). https://doi.org/10.1038/sj.leu.2403870

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