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Somatic mutations associated with leukemic progression of familial platelet disorder with predisposition to acute myeloid leukemia

Leukemia volume 30, pages 999–1002 (2016)Cite this article

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The familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) is an autosomal dominant disorder characterized by germline RUNX1 alterations. Missense, nonsense and frameshift mutations as well as intragenic duplications and large deletions of RUNX1 (21q22) have been reported in less than 45 pedigrees. Transformation to acute leukemia (AL) occurs with an incomplete penetrance and at a variable age in FPD/AML patients, suggesting that germline RUNX1 mutations alone are insufficient to induce AL. Thus this disorder represents a unique model to study leukemic progression. RUNX1 mutation could be considered like an inherited ‘first hit’, leading to a preleukemic state, but additional genetic alterations are required for the formation of fully transformed leukemic cells. To date, the most frequent additional event implicates an acquired mutation in the second allele of RUNX1.1 Despite this, recurrent mutations coinciding with transformation to AL are not yet well defined. Recently, somatic mutations in the cell cycle regulator CDC25C were identified in 53% of FPD/AML patients. CDC25C mutations appeared to occur in the preleukemic clone, and subsequent mutations in other genes, such as GATA2, coincided with leukemia progression.2 Moreover, a number of somatic mutations have been recently described to significantly co-occur with somatic RUNX1 aberrations in AML, including mutations in the Polycomb-associated genes ASXL1/2 in t(8;21) AML, as well as in RUNX1-mutated AML.3 Intriguingly, an acquired ASXL1 mutation has been also described in a FPD/AML patient who developed T-ALL.4 Given these recent discoveries and the lack of recurrent mutations known to coincide with leukemic progression of FPD/AML patients, we explored the status of 44 AML-associated genes in 25 individuals from 15 FPD/AML pedigrees. Interestingly, we identified a second alteration of RUNX1 in all patients who developed AML, in contrast to patients who developed T-ALL.

The FPD/AML patients were identified from 2005 to 2014 (Supplementary Material, Supplementary Figure S1A), and biological samples were collected after informed consent, in accordance with the Declaration of Helsinki. Genomic DNA was extracted from peripheral blood or bone marrow mononuclear cells, using standard procedures. Next-generation sequencing (NGS) was performed at thrombocytopenia stage if the patients were thrombocytopenic or at leukemia stage if they developed AL. For one patient, samples for both stages have been collected (patient 9). For patients who progressed to AL, samples were also collected at the time of complete remission to confirm acquired status of mutations. NGS was performed using a custom-designed 44 gene panel (MiSeq, Illumina, San Diego, CA, USA), including the entire coding region of ASXL 1, ASXL2, CDC25C, BCOR, BCORL1, BRAF, CSF3R, CALR, CBL, CEBPA, DNMT3A, ETV6, EZH2, FBXW7, FLT3, GATA1, GATA2, IDH1, IDH2, JAK2, JAK3, KIT, KRAS, MPL, NIPBL, NPM1, NOTCH1, NRAS, PHF6, PTEN, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC1A, SMC3, SRSF2, STAG2, TET2, TP53, U2AF1, WT1 and ZRSR2, with a median depth of 2692 ×. For CDC25C, the entire coding region was covered with a mean depth of 2633 × (range: 1837–3656). Hotspot locations at codons 233–234 described by Yoshimi et al.2 were visually checked without any filters. Depth at these codons was >3000 for all patients. FLT3 internal tandem duplication (FLT3-ITD) was detected as previously described.5 RUNX1 loss of heterozygosity was deducted from variant allele frequencies (VAF) found by NGS and standard cytogenetic analysis. For the patient 25, quality of DNA did not allow a good quantification of the VAF. For the patients 5, 7 and 24, NGS was not performed at AL stage owing to a lack of DNA. We report here the mutations already described for these patients.1 Cytogenetic G-banding analysis was performed according to standard methods in each center. Comparative genomic hybridization array analysis was performed for patients 8 and 21 as previously described.1, 6

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Acknowledgements

We thank all patients, families and clinicians for their participation. The work was supported by PRTK 2009-330. IA-D is supported by a postdoctoral fellowship from the Association pour la recherche sur le cancer. OA-W is supported by an NIH K08 Clinical Investigator Award (1K08CA160647-01), a US Department of Defense Postdoctoral Fellow Award in Bone Marrow Failure Research (W81XWH-12-1-0041), the Josie Robertson Investigator Program and a Damon Runyon Clinical Investigator Award with support from the Evans Foundation. J-BM is supported by the Fondation de France.

Author contributions

N Duployez, MB, SG, AR and CP performed genetic analysis and analyzed mutational data. IA-D, N Duployez, NB and CP conceptualized the idea, designed the research and analyzed data. N Dhédin, DR, BN, CB, TL, M-JM, RF, P-GH, HR, VL-C and CP provided samples and data. IA-D, N Duployez, J-BM, OA-W and CP wrote the manuscript, which was approved by all the authors.

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Author notes

  1. I Antony-Debré, N Duployez, V Latger-Cannard and C Preudhomme: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA

    I Antony-Debré

  2. INSERM UMR1170, Institut Gustave Roussy, University Paris-Sud 11, Equipe labellisée Ligue Contre le Cancer, Villejuif, France

    I Antony-Debré, J-B Micol, R Favier & H Raslova

  3. Laboratory of Hematology, University Lille Nord de France, Lille, France

    N Duployez, M Bucci, S Geffroy, A Renneville & C Preudhomme

  4. INSERM UMR-S 1172, Lille, France

    N Duployez, S Geffroy, A Renneville, C Berthon & C Preudhomme

  5. Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA

    J-B Micol & O Abdel-Wahab

  6. Department of Hematology, Institut Gustave Roussy, Villejuif, France

    J-B Micol

  7. Department of Hematology, Hôpital Saint-Louis, University Paris Diderot, Paris, France

    N Boissel, N Dhédin & D Réa

  8. Department of Pediatric Hematology, CHU of Lille, Lille, France

    B Nelken

  9. Department of Hematology, CHU of Lille, Lille, France

    C Berthon

  10. Department of Pediatric Hematology, Hôpital Robert Debré, Paris, France

    T Leblanc

  11. Department of Molecular Biology and Cytogenetics, Institut Paoli-Calmettes, Marseille, France

    M-J Mozziconacci

  12. Laboratory of Hematology, Hôpital Trousseau, Paris, France

    R Favier

  13. Department of Hematology Research, Instituto de Investigaciones Médicas Alfredo Lanari, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Cientificas y Technicas, Buenos Aires, Argentina

    P G Heller

  14. Laboratory of Hematology, Nancy University Hospital, Nancy, France

    V Latger-Cannard

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  1. I Antony-Debré
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  2. N Duployez
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Correspondence to C Preudhomme.

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Antony-Debré, I., Duployez, N., Bucci, M. et al. Somatic mutations associated with leukemic progression of familial platelet disorder with predisposition to acute myeloid leukemia. Leukemia 30, 999–1002 (2016). https://doi.org/10.1038/leu.2015.236

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