Skip to main content

Thank you for visiting 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.

Acute myeloid leukemia

Rare germline variant contributions to myeloid malignancy susceptibility

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

Access options

Rent or buy this article

Get just this article for as long as you need it


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

Fig. 1: Myeloperoxidase (MPO) as a candidate susceptibility gene in myeloid malignancy.
Fig. 2: Autosomal recessive genes and Fanconi anemia genes have higher overall and truncating rare germline variant burden.


  1. 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;126:2484–90.

    Article  CAS  Google Scholar 

  2. Godley LA, Shimamura A. Genetic predisposition to hematologic malignancies: management and surveillance. Blood. 2017;130:424–32.

    Article  CAS  Google Scholar 

  3. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.

    Article  CAS  Google Scholar 

  4. Polprasert C, Schulze I, Sekeres MA, Makishima H, Przychodzen B, Hosono N, et al. Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell. 2015;27:658–70.

    Article  CAS  Google Scholar 

  5. Guidugli L, Johnson AK, Alkorta-Aranburu G, Nelakuditi V, Arndt K, Churpek JE, et al. Clinical utility of gene panel-based testing for hereditary myelodysplastic syndrome/acute leukemia predisposition syndromes. Leukemia. 2017;31:1226–9.

    Article  CAS  Google Scholar 

  6. Cheah JJC, Hahn CN, Hiwase DK, Scott HS, Brown AL. Myeloid neoplasms with germline DDX41 mutation. Int J Hematol. 2017;106:163–74

    Article  CAS  Google Scholar 

  7. Zhang MY, Churpek JE, Keel SB, Walsh T, Lee MK, Loeb KR, et al. Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nat Genet. 2015;47:180–5.

    Article  CAS  Google Scholar 

  8. 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;23:166–75.

    Article  CAS  Google Scholar 

  9. 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;99:1364–72.

    Article  CAS  Google Scholar 

  10. Tyner JW, Tognon CE, Bottomly D, Wilmot B, Kurtz SE, Savage SL, et al. Functional genomic landscape of acute myeloid leukaemia. Nature. 2018;562:526–31.

    Article  CAS  Google Scholar 

  11. Schmidt T, Samaras P, Frejno M, Gessulat S, Barnert M, Kienegger H, et al. ProteomicsDB. Nucleic Acids Res. 2018;46:D1271–D81.

    Article  CAS  Google Scholar 

  12. Consortium GT Human genomics. The genotype-tissue expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015;348:648–60.

    Article  Google Scholar 

  13. Marchetti C, Patriarca P, Solero GP, Baralle FE, Romano M. Genetic characterization of myeloperoxidase deficiency in Italy. Hum Mutat. 2004;23:496–505.

    Article  CAS  Google Scholar 

  14. Sun BB, Maranville JC, Peters JE, Stacey D, Staley JR, Blackshaw J, et al. Genomic atlas of the human plasma proteome. Nature 2018;558:73–9.

    Article  CAS  Google Scholar 

  15. Astle WJ, Elding H, Jiang T, Allen D, Ruklisa D, Mann AL, et al. The allelic landscape of human blood cell trait variation and links to common complex disease. Cell. 2016;167:1415–29 e19.

    Article  CAS  Google Scholar 

Download references


The authors with to acknowledge the individuals and families that were part of the study presented here, as well as researchers who made the exomes and metadata available to us. This study makes use of data generated by the Cancer Genomics Project at the University of Tokyo, the International Cancer Genome Consortium, the St. Jude Children’s Research Hospital Genomes for Kids Study, St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project, the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative managed by the NCI, The Cancer Genome Atlas. This work was supported in part by American Cancer Society grant 123436-RSG-12–159–01-DMC (TL), US National Institute of Health (NIH) grant R35 HL135795 (JPM), the Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Spain (PI/17/0575), 2017 SGR288 (GRC) Generalitat de Catalunya, and CERCA Program/Generalitat de Catalunya, Fundació Internacional Josep Carreras and from Celgene International (FS). The research leading to this work has received funding from “la Caixa” Foundation (FS). This work made use of the High Performance Computing Resource in the Core Facility for Advanced Research Computing at Case Western Reserve University.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Thomas LaFramboise.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, S.T., Wang, J., Wei, R. et al. Rare germline variant contributions to myeloid malignancy susceptibility. Leukemia 34, 1675–1678 (2020).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links