Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Chronic Myeloproliferative Neoplasias

RUNX1 mutations are frequent in chronic myelomonocytic leukemia and mutations at the C-terminal region might predict acute myeloid leukemia transformation

Abstract

Runt-related transcription factor 1 (RUNX1) is essential for normal hematopoiesis. RUNX1 mutations have rarely been reported in chronic myelomonocytic leukemia (CMML). We examined RUNX1 mutations in 81 patients with CMML at initial diagnosis. Mutational analysis was performed on bone marrow samples by direct sequencing of all reverse transcription PCR products amplified with three primer pairs that cover the entire coding sequences of RUNX1b. Thirty-two RUNX1 mutations were detected in 30 patients (37%); 23 mutants were located in the N-terminal part and 9 in the C-terminal region. The mutations consisted of 9 missense, 1 silent, 7 nonsense and 15 frameshift mutations. Two patients had biallelic heterozygous mutations. There was no difference in overall survival between patients with and without RUNX1 mutations, but a trend of higher risk of acute myeloid leukemia (AML) progression was observed in mutation-positive patients (16/30 vs 17/51, P=0.102), especially in patients with C-terminal mutations (P=0.023). The median time to AML progression was 6.8 months in patients with C-terminal mutations compared with 28.3 months in those without mutations (P=0.022). This study showed for the first time a high frequency of RUNX1 mutations in CMML. C-terminal mutations might be associated with a more frequent and rapid AML transformation.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982; 51: 189–199.

    Article  CAS  PubMed  Google Scholar 

  2. Jaffe ES, Harris NL, Stein H, Vardiman JW . World Health Organization Classification of Tumors: Pathology & Genetics Tumors of Haematopoietic and lymphoid tissues. IARC Press: Lyon, 2001, pp 45–52.

    Google Scholar 

  3. Padua RA, Guinn BA, Al-Sabah AI, Smith M, Taylor C, Pettersson T et al. RAS, FMS and p53 mutations and poor clinical outcome in myelodysplasias: a 10-year follow-up. Leukemia 1998; 12: 887–892.

    Article  CAS  PubMed  Google Scholar 

  4. Hirsch-Ginsberg C, LeMaistre AC, Kantarjian H, Talpaz M, Cork A, Freireich EJ et al. RAS mutations are rare events in Philadelphia chromosome-negative/bcr gene rearrangement-negative chronic myelogenous leukemia, but are prevalent in chronic myelomonocytic leukemia. Blood 1990; 76: 1214–1219.

    CAS  PubMed  Google Scholar 

  5. Cross NC, Reiter A . Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Leukemia 2002; 16: 1207–1212.

    Article  CAS  PubMed  Google Scholar 

  6. Shih LY, Huang CF, Wang PN, Wu JH, Lin TL, Dunn P et al. Acquisition of FLT3 or N-ras mutations is frequently associated with progression of myelodysplastic syndrome to acute myeloid leukemia. Leukemia 2004; 18: 466–475.

    Article  CAS  PubMed  Google Scholar 

  7. Shih LY, Lin TL, Wang PN, Wu JH, Dunn P, Kuo MC et al. Internal tandem duplication of fms-like tyrosine kinase 3 is associated with poor outcome in patients with myelodysplastic syndrome. Cancer 2004; 101: 989–998.

    Article  CAS  PubMed  Google Scholar 

  8. Shih LY, Huang CF, Lin TL, Wu JH, Wang PN, Dunn P et al. Heterogeneous patterns of CEBPα mutation status in the progression of myelodysplastic syndrome and chronic myelomonocytic leukemia to acute myeloid leukemia. Clin Cancer Res 2005; 11: 1821–1826.

    Article  CAS  PubMed  Google Scholar 

  9. Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR . AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 1996; 84: 321–330.

    Article  CAS  PubMed  Google Scholar 

  10. Wang Q, Stacy T, Binder M, Marin-Padilla M, Sharpe AH, Speck NA . Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. Proc Natl Acad Sci USA 1996; 93: 3444–3449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Asou N . The role of a Runt domain transcription factor AML1/RUNX1 in leukemogenesis and its clinical implications. Crit Rev Oncol Hematol 2003; 45: 129–150.

    Article  PubMed  Google Scholar 

  12. Speck NA, Gilliland DG . Core-binding factors in haematopoiesis and leukaemia. Nat Rev Cancer 2002; 2: 502–513.

    Article  CAS  PubMed  Google Scholar 

  13. Osato M, Asou N, Abdalla E, Hoshino K, Yamasaki H, Okubo T et al. Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2alphaB gene associated with myeloblastic leukemias. Blood 1999; 93: 1817–1824.

    CAS  PubMed  Google Scholar 

  14. Roumier C, Eclache V, Imbert M, Davi F, MacIntyre E, Garand R et al. M0 AML, clinical and biologic features of the disease, including AML1 gene mutations: a report of 59 cases by the Groupe Francais d’Hematologie Cellulaire (GFHC) and the Groupe Francais de Cytogenetique Hematologique (GFCH). Blood 2003; 101: 1277–1283.

    Article  CAS  PubMed  Google Scholar 

  15. Harada H, Harada Y, Tanaka H, Kimura A, Inaba T . Implications of somatic mutations in the AML1 gene in radiation-associated and therapy-related myelodysplastic syndrome/acute myeloid leukemia. Blood 2003; 101: 673–680.

    Article  CAS  PubMed  Google Scholar 

  16. Christiansen DH, Andersen MK, Pedersen-Bjergaard J . Mutations of AML1 are common in therapy-related myelodysplasia following therapy with alkylating agents and are significantly associated with deletion or loss of chromosome arm 7q and with subsequent leukemic transformation. Blood 2004; 104: 1474–1481.

    Article  CAS  PubMed  Google Scholar 

  17. Harada H, Harada Y, Niimi H, Kyo T, Kimura A, Inaba T . High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia. Blood 2004; 103: 2316–2324.

    Article  CAS  PubMed  Google Scholar 

  18. Steensma DP, Gibbons RJ, Mesa RA, Tefferi A, Higgs DR . Somatic point mutations in RUNX1/CBFA2/AML1 are common in high-risk myelodysplastic syndrome, but not in myelofibrosis with myeloid metaplasia. Eur J Haematol 2005; 74: 47–53.

    Article  CAS  PubMed  Google Scholar 

  19. Nakao M, Horiike S, Fukushima-Nakase Y, Nishimura M, Fujita Y, Taniwaki M et al. Novel loss-of-function mutations of the haematopoiesis-related transcription factor, acute myeloid leukaemia 1/runt-related transcription factor 1, detected in acute myeloblastic leukaemia and myelodysplastic syndrome. Br J Haematol 2004; 125: 709–719.

    Article  CAS  PubMed  Google Scholar 

  20. Osato M . Point mutations in the RUNX1/AML1 gene: another actor in RUNX leukemia. Oncogene 2004; 23: 4284–4296.

    Article  CAS  PubMed  Google Scholar 

  21. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89: 2079–2088.

    CAS  PubMed  Google Scholar 

  22. Shih LY, Huang CF, Wu JH, Lin TL, Dunn P, Wang PN et al. Internal tandem duplication of FLT3 in relapsed acute myeloid leukemia: a comparative analysis of bone marrow samples from 108 adult patients at diagnosis and relapse. Blood 2002; 100: 2387–2392.

    Article  CAS  PubMed  Google Scholar 

  23. Hopfner KP, Eichinger A, Engh RA, Laue F, Ankenbauer W, Huber R et al. Crystal structure of a thermostable type B DNA polymerase from Thermococcus gorgonarius. Proc Natl Acad Sci USA 1999; 96: 3600–3605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet 1999; 23: 166–175.

    Article  CAS  PubMed  Google Scholar 

  25. Imai Y, Kurokawa M, Izutsu K, Hangaishi A, Takeuchi K, Maki K et al. Mutations of the AML1 gene in myelodysplastic syndrome and their functional implications in leukemogenesis. Blood 2000; 96: 3154–3160.

    CAS  PubMed  Google Scholar 

  26. Dicker F, Haferlach C, Kern W, Haferlach T, Schnittger S . Trisomy 13 is strongly associated with AML1/RUNX1 mutations and increased FLT3 expression in acute myeloid leukemia. Blood 2007; 110: 1308–1316.

    Article  CAS  PubMed  Google Scholar 

  27. Imai O, Kurokawa M, Izutsu K, Hangaishi A, Maki K, Ogawa S et al. Mutational analyses of the AML1 gene in patients with myelodysplastic syndrome. Leuk Lymphoma 2002; 43: 617–621.

    Article  CAS  PubMed  Google Scholar 

  28. Michaud J, Wu F, Osato M, Cottles GM, Yanagida M, Asou N et al. In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis. Blood 2002; 99: 1364–1372.

    Article  CAS  PubMed  Google Scholar 

  29. Harada H, Harada Y . Point mutations in the AML1/RUNX1 gene associated with myelodysplastic syndrome. Crit Rev Eukartyot Gene Expr 2005; 15: 183–196.

    Article  CAS  Google Scholar 

  30. Kanno T, Kanno Y, Chen LF, Ogawa E, Kim WY, Ito Y . Intrinsic transcriptional activation-inhibition domains of the polyomavirus enhancer binding protein 2/core binding factor alpha subunit revealed in the presence of the beta subunit. Mol Cell Biol 1998; 18: 2444–2454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kelly LM, Gilliland DG . Genetics of myeloid leukemias. Annu Rev Genomics Hum Genet 2002; 3: 179–198.

    Article  CAS  PubMed  Google Scholar 

  32. Preudhomme C, Warot-Loze D, Roumier C, Grardel-Duflos N, Garand R, Lai JL et al. High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2 alpha B gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21. Blood 2000; 96: 2862–2869.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by grants NHRI-EX95-9434SI, NHRI-EX96-9434SI and NHRI-EX97-9711SI from the National Health Research Institute (L-Y Shih), and grant MMH-E-97009 from the Mackay Memorial Hospital (D-C Liang). We thank Dr Po-Nan Wang and Dr Po Dunn for providing patient samples and Ms Yu-Feng Wang for secretarial assistance.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to L-Y Shih.

Additional information

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kuo, MC., Liang, DC., Huang, CF. et al. RUNX1 mutations are frequent in chronic myelomonocytic leukemia and mutations at the C-terminal region might predict acute myeloid leukemia transformation. Leukemia 23, 1426–1431 (2009). https://doi.org/10.1038/leu.2009.48

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2009.48

Keywords

This article is cited by

Search

Quick links