Abstract
Germline DDX41 mutations were recently reported to cause MDS/AML and donor-derived leukemia after transplantation. While previously described in Western countries, DDX41 variants have not been reported in a Southeast Asian population. We performed targeted sequencing of blood or bone marrow samples from 109 Thai patients with myeloid malignancies. Among the 109 patients (75 MDS, 8 MPN, 11 MDS/MPN and 15 AML), the most frequent mutations were in ASXL1 (17.4%), TET2 (16.5%) and SRSF2 (12.8%), respectively. DDX41 variants were detectable in six (5.5%) cases. Four patients exhibited three presumable germline DDX41 mutations: p.S21fs (n = 2), p.F235fs (n = 1), and p.R339H (n = 1). While p.S21fs was previously reported in myeloid neoplasm, the latter two variants have not been described. Two of these cases harbored concomitant probable germline/somatic DDX41 mutations (p.S21fs/p.R525H and p.R339H/p.K494T), while the other two patients carried only somatic mutations (p.R525H and p.F438L). The p.K494T and p.F438L variants have not been previously reported. In patients with DDX41 alterations, the diagnoses were MDS with excess blasts (4), secondary AML (1) and low-risk MDS (1). In conclusion, we identified DDX41 variants in Thai patients with myeloid malignancies in which these variants could be used to assess predisposition to MDS in Southeast Asia.
Similar content being viewed by others
References
Owen CJ, Toze CL, Koochin A, Forrest DL, Smith CA, Steven JM, et al. Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy. Blood. 2008;112:4639–45.
Churpek JE, Garcia JS, Madzo J, Jackson SA, Onel K, Godley LA. Identification and molecular characterization of a novel 3′ mutation in RUNX1 in a family with familial platelet disorder. Leuk Lymphoma. 2010;51:1931–5.
Tsai FY, Keller G, Kuo FC, Weiss M, Chen J, Rosenblatt M, et al. An early haematopoietic defect in mice lacking the transcription factor GATA-2. Nature. 1994;371:221–6.
Pabst T, Eyholzer M, Fos J, Mueller BU. Heterogeneity within AML with CEBPA mutations; only CEBPA double mutations, but not single CEBPA mutations are associated with favorable prognosis. Br J Cancer. 2009;100:1343–6.
Nickels EM, Soodalter J, Churpek JE, Godley LA. Recognizing familial myeloid leukemia in adults. Ther Adv Hematol. 2013;4:254–69.
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.
Lewinsohn M, Brown AL, Weinel LM, Phung C, Rafidi G, Lee MK, et al. Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies. Blood. 2016;127:1017–23.
Kobayashi S, Kobayashi A, Osawa Y, Nagao S, Takano K, Okada Y, et al. Donor cell leukemia arising from preleukemic clones with a novel germline DDX41 mutation after allogenic hematopoietic stem cell transplantation. Leukemia. 2017;31:1020–2.
Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122:3616–27.
Malcovati L, Karimi M, Papaemmanuil E, Ambaglio I, Jädersten M, Jansson M, et al. SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts. Blood. 2015;126:233–41.
Quesada AE, Routbort MJ, Dinardo CD, Bueso-Ramos CE, Kanagal-Shamanna R, Khoury JD, et al. DDX41 mutations in myeloid neoplasms are associated with male gender, TP53 mutations and high-risk disease. Am J Hematol. 2019. https://doi.org/10.1002/ajh.25486.
Acknowledgements
This research was supported by The Thailand Research Fund (RDG6050109), Ratchadapiseksompoj grant (RA60/099), research affair, Chulalongkorn University, grant from The Royal College of Physicians of Thailand (RCPT) and grant from Research Collaborations in Hematologic Malignancies and Hematopoietic Stem Cell Transplantation.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors have no conflicts of interest to disclose.
Statement of ethics
The study protocol has been approved by research institute’s committee on human research.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Polprasert, C., Takeda, J., Niparuck, P. et al. Novel DDX41 variants in Thai patients with myeloid neoplasms. Int J Hematol 111, 241–246 (2020). https://doi.org/10.1007/s12185-019-02770-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12185-019-02770-3