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Elucidation of a novel pathogenomic mechanism using genome-wide long mate-pair sequencing of a congenital t(16;21) in a series of three RUNX1-mutated FPD/AML pedigrees

Leukemia volume 26, pages 2151–2154 (2012)Cite this article

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Familial platelet disorder with propensity to develop myeloid malignancy (FPD/AML OMIM 601399) is an autosomal disorder characterized by quantitative and qualitative platelet anomalies and predisposition to MDS/AML, caused by germ line point mutations, deletions and duplications in RUNX1.1, 2, 3, 4 RUNX1 encodes a transcription factor essential for definitive hematopoiesis, containing an amino-terminal DNA binding domain (RUNT) and a carboxyl-terminal transactivation domain (TA). RUNX1 mutations act by either a dominant negatively interfering mechanism or by haploinsufficiency. Constitutional deletions spanning RUNX1 have been reported in isolated congenital or syndromic thrombocytopenia, stipulating copy number analysis (CNA) of RUNX1 next to sequencing.5, 6, 7, 8 Given clinical heterogeneity, vigilance in diagnosing FPD/AML is required, reducing the risk of stem cell transplantation (SCT) with carrier siblings.2, 3 Furthermore, the identification of a RUNX1 abnormality and the elucidation of the underlying pathogenomic mechanism may have implications for genetic counseling for recurrence risk of FPD/AML.

This study included two families with classical FPD/AML and one seemingly isolated case with storage pool deficiency (SPD), thrombocytopenia and AML. All patients were of Caucasian origin. For detailed clinical and hematological characteristics of the pedigrees, we refer to Supplemental Table S1. RUNX1 was analyzed by Sanger sequencing of coding exons 2–9 of gDNA using intronic primers.

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References

  1. 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 

  2. Buijs A, Poddighe P, van Wijk R, van Solinge W, Borst E, Verdonck L et al. A novel CBFA2 single-nucleotide mutation in familial platelet disorder with propensity to develop myeloid malignancies. Blood 2001; 98: 2856–2858.

    Article  CAS  PubMed  Google Scholar 

  3. Owen CJ, Toze CL, Koochin A, Forrest DL, Smith CA, Stevens JM et al. Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy. Blood 2008; 112: 4639–4645.

    Article  CAS  PubMed  Google Scholar 

  4. Jongmans MC, Kuiper RP, Carmichael CL, Wilkins EJ, Dors N, Carmagnac A et al. Novel RUNX1 mutations in familial platelet disorder with enhanced risk for acute myeloid leukemia: clues for improved identification of the FPD/AML syndrome. Leukemia 2010; 24: 242–246.

    Article  CAS  PubMed  Google Scholar 

  5. Shinawi M, Erez A, Shardy DL, Lee B, Naeem R, Weissenberger G et al. Syndromic thrombocytopenia and predisposition to acute myelogenous leukemia caused by constitutional microdeletions on chromosome 21q. Blood 2008; 112: 1042–1047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Beri-Dexheimer M, Latger-Cannard V, Philippe C, Bonnet C, Chambon P, Roth V et al. Clinical phenotype of germline RUNX1 haploinsufficiency: from point mutations to large genomic deletions. Eur J Hum Genet 2008; 16: 1014–1018.

    Article  CAS  PubMed  Google Scholar 

  7. van der Crabben S, van Binsbergen E, Ausems M, Poot M, Bierings M, Buijs A . Constitutional RUNX1 deletion presenting as non-syndromic thrombocytopenia with myelodysplasia: 21q22 ITSN1 as a candidate gene in mental retardation. Leuk Res 2010; 34: e8–e12.

    Article  CAS  PubMed  Google Scholar 

  8. Owen C . Insights into familial platelet disorder with propensity to myeloid malignancy (FPD/AML). Leuk Res 2010; 34: 141–142.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. 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 

  11. Kloosterman WP, Guryev V, van Roosmalen M, Duran KJ, de Bruijn E, Bakker SC et al. Chromothripsis as a mechanism driving complex de novo structural rearrangements in the germline. Hum Mol Genet 2011; 20: 1916–1924.

    Article  CAS  PubMed  Google Scholar 

  12. von Goessel H, Jacobs U, Semper S, Krumbholz M, Langer T, Keller T et al. Cluster analysis of genomic ETV6-RUNX1 (TEL-AML1) fusion sites in childhood acute lymphoblastic leukemia. Leuk Res 2009; 33: 1082–1088.

    Article  CAS  PubMed  Google Scholar 

  13. Nottingham WT, Jarratt A, Burgess M, Speck CL, Cheng JF, Prabhakar S et al. Runx1-mediated hematopoietic stem-cell emergence is controlled by a Gata/Ets/SCL-regulated enhancer. Blood 2007; 110: 4188–4197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bee T, Ashley EL, Bickley SR, Jarratt A, Li PS, Sloane-Stanley J et al. The mouse Runx1 +23 hematopoietic stem cell enhancer confers hematopoietic specificity to both Runx1 promoters. Blood 2009; 113: 5121–5124.

    Article  CAS  PubMed  Google Scholar 

  15. Liu L, Ishihara K, Ichimura T, Fujita N, Hino S, Tomita S et al. MCAF1/AM is involved in Sp1-mediated maintenance of cancer-associated telomerase activity. J Biol Chem 2009; 284: 5165–5174.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the patients and family members who participated in this study, as well as the technicians of the section Genome Diagnostics of the Department of Medical Genetics for excellent technical support. Eric Borst and Richard Zewald are acknowledged for the initial sequencing experiments. Nine Knoers, Dick Lindhout, Tom Letteboer, Lars van der Veken (UMC Utrecht) and Marella de Bruijn (University of Oxford, United Kingdom) are particularly thanked for critically reading the manuscript and useful suggestions. Ivo Renkens is thanked for SOLiD sequencing and Edwin Cuppen for facilitating GWLMPS.

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Authors and Affiliations

  1. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

    A Buijs, M Poot, S van der Crabben, B van der Zwaag, E van Binsbergen, M J van Roosmalen, M Tavakoli-Yaraki, M van Gijn & W P Kloosterman

  2. Department of Internal Medicine, St Antonius Hospital, Nieuwegein, The Netherlands

    O de Weerdt

  3. Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands

    H K Nieuwenhuis

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  1. A Buijs
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Correspondence to A Buijs.

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Buijs, A., Poot, M., van der Crabben, S. et al. Elucidation of a novel pathogenomic mechanism using genome-wide long mate-pair sequencing of a congenital t(16;21) in a series of three RUNX1-mutated FPD/AML pedigrees. Leukemia 26, 2151–2154 (2012). https://doi.org/10.1038/leu.2012.79

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