Skip to main content

C-terminal RUNX1 mutation in familial platelet disorder with predisposition to myeloid malignancies

International Journal of Hematology volume 108, pages 652–657 (2018)Cite this article

Abstract

Here we report a C-terminal RUNX1 mutation in a family with platelet disorder and predisposition to myeloid malignancies. We identified the mutation c.866delG:p.Gly289Aspfs*22 (NM_001754) (RUNX1 b-isoform NM_001001890; c.785delG:p.Gly262Aspfs*22) using exome sequencing of samples obtained from eight members of a single family. The mutation found in our pedigree is within exon eight and the transactivation domain of RUNX1. One of the affected individuals developed myelodysplastic syndrome (MDS), which progressed to acute myelogenous leukemia (AML). A search for the second hit which led to the development of MDS and later AML in this individual revealed the PHF6 gene variant (exon9:c.872G > A:p.G291E; NM_001015877), BCORL1 (exon3:c.1111A > C:p.T371P; NM_001184772) and BCOR gene variant (exon4:c.2076dupT:p.P693fs; NM_001123383), which appear to be very likely second hits participating in the progression to myeloid malignancy.

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

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Schlegelberger B, Heller PG. RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM). Semin Hematol. 2017;54(2):75–80.

    Article  Google Scholar 

  2. Hayashi Y, Harada Y, Huang G, Harada H. Myeloid neoplasms with germ line RUNX1 mutation. Int J Hematol. 2017;106:183–8.

    CAS  Article  Google Scholar 

  3. 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;93:1817–24.

    CAS  PubMed  Google Scholar 

  4. 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(2):166–75.

    CAS  Article  Google Scholar 

  5. Yoshimi A, Toya T, Kawazu M, Ueno T, Tsukamoto A, Iizuka H, Nakagawa M, et al. Recurrent CDC25C mutations drive malignant transformation in FPD/AML. Nat Commun. 2014;5:4770. https://doi.org/10.1038/ncomms5770.

    CAS  Article  PubMed  Google Scholar 

  6. Shiba N, Hasegawa D, Park MJ, Murata C, Sato-Otsubo A, Ogawa C, et al. CBL mutation in chronic myelomonocytic leukemia secondary to familial platelet disorder with propensity to develop acute myeloid leukemia (FPD/AML). Blood. 2012;119(11):2612–4.

    CAS  Article  Google Scholar 

  7. Bellissimo DC, Speck NA. RUNX1 mutations in inherited and sporadic leukemia. Front Cell Dev Biol. 2017;5:111.

    Article  Google Scholar 

  8. Van Vlierberghe P, Patel J, Abdel-Wahab O, Lobry C, Hedvat CV, Balbin M, et al. PHF6 mutations in adult acute myeloid leukemia. Leukemia. 2011;25(1):130–4.

    Article  Google Scholar 

  9. Terada K, Yamaguchi H, Ueki T, Usuki K, Kobayashi Y, Tajika K, et al. Usefulness of BCOR gene mutation as a prognostic factor in acute myeloid leukemia with intermediate cytogenetic prognosis. Genes Chromosom Cancer. 2018. https://doi.org/10.1002/gcc.22542.

    Article  PubMed  Google Scholar 

  10. Damm F, Chesnais V, Nagata Y, Yoshida K, Scourzic L, Okuno Y, et al. and BCORL1 mutations in myelodysplastic syndromes and related disorders. BCOR. 2013;122(18):3169–77. Blood.

    CAS  Google Scholar 

  11. Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, et al. Frequent pathways mutations of splicing machinery in myelodysplasia. Nature. 2011;478(7367):64–9.

    CAS  Article  Google Scholar 

  12. Mori T, Nagata Y, Makishima H, Sanada M, Shiozawa Y, Kon A, et al. Somatic PHF6 mutations in 1760 cases with various myeloid neoplasms. Leukemia. 2016;30(11):2270–3.

    CAS  Article  Google Scholar 

  13. Ng IK, Lee J, Ng C, Kosmo B, Chiu L, Seah E et al. Preleukemic and second-hit mutational events in an acute myeloid leukemia patient with a novel germline RUNX1 mutation. Biomark Res. 2018;6:16. https://doi.org/10.1186/s40364-018-0130-2.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Klambauer G, Schwarzbauer K, Mayr A, Mitterecker A, Clevert D, Bodenhofer U, Hochreiter S. cn.MOPS: Mixture of Poissons for discovering copy number variations in next generation sequencing data with a low false discovery rate. Nucleic Acids Res. 2012;40:e69. https://doi.org/10.1093/nar/gks003.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Gaidzik VI, Bullinger L, Schlenk RF, Zimmermann AS, Rock J, Paschka P, et al. RUNX1 mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group. J Clin Oncol. 2011;29:1364–72.

    Article  Google Scholar 

  16. Schmit JM, Turner DJ, Hromas RA, Wingard JR, Brown RA, Li Y, et al. Two novel RUNX1 mutations in a patient with congenital thrombocytopenia that evolved into a high grade myelodysplastic syndrome. Leuk Res Rep. 2015;4(1):24–7.

    PubMed  PubMed Central  Google Scholar 

  17. Yoshimi A, Toya T, Nannya Y, Takaoka K, Kirito K, Ito E, et al. Spectrum of clinical and genetic features of patients with inherited platelet disorder with suspected predisposition to hematological malignancies: a nationwide survey in Japan. Ann Oncol. 2016;27:887–95.

    CAS  Article  Google Scholar 

  18. Liew E, Owen C. Familial myelodysplastic syndromes: a review of the literature. Haematologica. 2011;96:1536–42.

    Article  Google Scholar 

  19. Matheny CJ, Speck ME, Cushing PR, Zhou Y, Corpora T, Regan M,et al. Disease mutations in RUNX1 and RUNX2 create nonfunctional, dominant-negative, or hypomorphic alleles. EMBOJ. 2007;26:1163–75.

    CAS  Article  Google Scholar 

  20. Ripperger T, Steinemann D, Gohring G, Finke J, Niemeyer CM, StrahmB,et al. A novel pedigree with heterozygous germline RUNX1 mutation causing familial MDS-related AML: can these families serve as a multistep model for leukemic transformation? Leukemia. 2009;23:1364–6.

    CAS  Article  Google Scholar 

  21. Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, et al. The human gene mutation database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136(6):665–77.

    CAS  Article  Google Scholar 

  22. Satoh Y, Matsumura I, Tanaka H, Ezoe S, Fukushima K, Tokunaga M, et al. AML1/RUNX1 works as a negative regulator of c-Mpl in hematopoietic stem cells. J Biol Chem. 2008;283(44):30045–56.

    CAS  Article  Google Scholar 

  23. Churpek JE, Pyrtel K, Kanchi KL, Shao J, Koboldt D, Miller CA, et al. Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia. Blood. 2015;126(22):2484–90.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

Supported by Ministry of Health of the Czech Republic, Grant No. 16-29447A. All rights reserved.

Author information

Authors and Affiliations

  1. Central European Institute of Technology (CEITEC), University Hospital, Masaryk University, Brno, Czech Republic

    Kateřina Staňo Kozubík, Lenka Radová, Michaela Pešová, Kamila Réblová, Jakub Trizuljak, Karla Plevová, Jiří Mayer, Šárka Pospíšilová & Michael Doubek

  2. Department of Internal Medicine, Hematology and Oncology, University Hospital, Masaryk University, Brno, Czech Republic

    Jakub Trizuljak, Jiří Mayer, Šárka Pospíšilová & Michael Doubek

  3. Department of Pediatric Hematology, University Hospital, Brno, Czech Republic

    Veronika Fiamoli

  4. Department of Hematologic Oncology, University Hospital, Ostrava, Czech Republic

    Jaromír Gumulec

  5. Department of Hematologic Oncology, University Hospital, Palacký University, Olomouc, Czech Republic

    Helena Urbánková & Tomáš Szotkowski

Authors
  1. Kateřina Staňo Kozubík
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lenka Radová
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michaela Pešová
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kamila Réblová
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jakub Trizuljak
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Karla Plevová
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Veronika Fiamoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jaromír Gumulec
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Helena Urbánková
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tomáš Szotkowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jiří Mayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Šárka Pospíšilová
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Michael Doubek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Doubek.

Ethics declarations

Conflict of interest

The authors have had the costs of participating in certain scientific meetings reimbursed by the pharmaceutical industry.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (XLSX 13 KB)

Supplementary material 2 (XLSX 13 KB)

About this article

Verify currency and authenticity via CrossMark

Cite this article

Staňo Kozubík, K., Radová, L., Pešová, M. et al. C-terminal RUNX1 mutation in familial platelet disorder with predisposition to myeloid malignancies. Int J Hematol 108, 652–657 (2018). https://doi.org/10.1007/s12185-018-2514-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-018-2514-3

Keywords

  • Familial platelet disorder with predisposition to myeloid malignancies
  • Inherited thrombocytopenia
  • RUNX1