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.

  • Correspondence
  • Published:

Donor cell leukemia arising from preleukemic clones with a novel germline DDX41 mutation after allogenic hematopoietic stem cell transplantation

Leukemia volume 31, pages 1020–1022 (2017)Cite this article

Subjects

Berger et al.1 provided the first report of DDX41 mutations that contributed to the development of donor cell leukemia (DCL). Germline mutations in DDX41, a gene encoding a DEAD-box RNA helicase, have recently been discovered in myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) pedigrees associated with a hereditary predisposition to MDS/AML due to defective tumor suppression by the mutant.2 Unlike similar cancers that present at younger ages (<45 years), DDX41 pedigrees have a median onset at 62 years.1, 2 DCL was first described in 1971 as a relapse following allogenic hematopoietic stem cell transplantation (allo-HSCT). Wiseman et al.3 suggested that DCL could account for up to 5% of all post-transplant leukemias. Although the etiology remains unknown, donor hematopoietic stem cells may be preleukemic at transplantation.4, 5, 6 Donors and recipients are related in 80% of cases, so a shared genetic predisposition may be associated with a higher potential for DCL.3 Berger et al.1 used whole-exome sequencing and a targeted sequencing approach for a panel of the most recurrently mutated genes in AML and concluded that DDX41 mutations might contribute to AML development against the background of other mutations or a second somatic DDX41 mutation. Around this same time, we also performed genomic analysis of a DCL that developed following allo-HSCT between a patient with MDS/AML and an HLA-matched healthy sibling donor, both with novel DDX41 germline mutations. To detect mutations that contributed to the DCL development in a DDX41 pedigree, we undertook a combination of whole-exome sequencing and targeted sequencing of genes that were newly screened in DCL cells or were reported to have a potential role in the pathogenesis of MDS/AML in the bone marrow (BM) niche.7

The patient was a 49-year-old man, first presented with a 6-month history of thrombocytopenia, and diagnosed with MDS with excess blasts-2 (EB2) and a normal karyotype. His father and uncle had died in their seventies from MDS and AML, respectively. He underwent myeloablative allogenic BM transplantation (BMT) from his HLA-identical brother after providing informed consent (which specifically mentioned the risk of DCL). Seventeen months later, he became thrombocytopenic, and BM aspiration showed MDS/EB2 relapse that subsequently developed into AML. Short tandem repeat analysis showed complete donor chimerism, demonstrating that DCL had developed from the allogenic BM of the sibling. After receiving a second BMT from an unrelated HLA-matched donor, the patient has remained in complete remission for 29 months. His sibling donor has remained healthy for 56 months following the initial donation.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1

References

  1. Berger G, van den Berg E, Sikkema-Raddatz B, Abbott KM, Sinke RJ, Bungener LB et al. Re-emergence of acute myeloid leukemia in donor cells following allogeneic transplantation in a family with a germline DDX41 mutation. Leukemia 2017; 31: 520–522.

    Article  CAS  PubMed  Google Scholar 

  2. 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: 658–670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wiseman DH . Donor cell leukemia: a review. Biol Blood Marrow Transplant 2011; 17: 771–789.

    Article  PubMed  Google Scholar 

  4. Hahn CN, Ross DM, Feng J, Beligaswatte A, Hiwase DK, Parker WT et al. A tale of two siblings: two cases of AML arising from a single pre-leukemic DNMT3A mutant clone. Leukemia 2015; 29: 2101–2104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hirsch P, Mamez AC, Belhocine R, Lapusan S, Tang R, Suner L et al. Clonal history of a cord blood donor cell leukemia with prenatal somatic JAK2 V617F mutation. Leukemia 2016; 30: 1756–1759.

    Article  CAS  PubMed  Google Scholar 

  6. Gondek LP, Zheng G, Ghiaur G, DeZern AE, Matsui W, Yegnasubramanian S et al. Donor cell leukemia arising from clonal hematopoiesis after bone marrow transplantation. Leukemia 2016; 30: 1916–1920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bulycheva E, Rauner M, Medyouf H, Theurl I, Bornhauser M, Hofbauer LC et al. Myelodysplasia is in the niche: novel concepts and emerging therapies. Leukemia 2015; 29: 259–268.

    Article  CAS  PubMed  Google Scholar 

  8. Adams PD, Jasper H, Rudolph KL . Aging-induced stem cell mutations as drivers for disease and cancer. Cell Stem Cell 2015; 16: 601–612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Naro C, Bielli P, Pagliarini V, Sette C . The interplay between DNA damage response and RNA processing: the unexpected role of splicing factors as gatekeepers of genome stability. Front Genet 2015; 6: 142.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the patient’s family for their trust.

Author information

Authors and Affiliations

  1. Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan

    S Kobayashi, A Kobayashi, Y Osawa, S Nagao, K Takano, Y Okada, N Tachi, M Teramoto, T Kawamura, T Horiuchi, S Kato, T Maekawa, T Yamamura, J Watanabe, K Sato & F Kimura

  2. Department of Hematology, Juntendo University, School of Medicine, Tokyo, Japan

    Y Harada & H Harada

Authors
  1. S Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Osawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Nagao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Takano
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y Okada
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. N Tachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Teramoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. T Kawamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. T Horiuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. S Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. T Maekawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. T Yamamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. J Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Y Harada
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. H Harada
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. K Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. F Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Kobayashi.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kobayashi, S., Kobayashi, A., Osawa, Y. et al. Donor cell leukemia arising from preleukemic clones with a novel germline DDX41 mutation after allogenic hematopoietic stem cell transplantation. Leukemia 31, 1020–1022 (2017). https://doi.org/10.1038/leu.2017.44

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2017.44

This article is cited by

Search

Advanced search

Quick links