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Germline and Somatic Defects in DDX41 and its Impact on Myeloid Neoplasms

  • Germline Predisposition to Myeloid Neoplasms (M Patnaik, Section Editor)
  • Published:
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Abstract

Purpose of Review

While DDX41 mutation (m) is one of the most prevalent predisposition genes in adult myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), most patients do not always present with a family history of MDS/AML. In this review, we will be highlighting epidemiological data on DDX41m, roles of DDX41 in oncogenesis, mechanisms of clonal evolution with somatic DDX41m, and clinical phenotypes and management of MDS/AML in patients harboring DDX41m.

Recent Findings

DDX41 encodes a DEAD-box helicase protein that is considered essential for cell growth and viability. High incidence of myeloid malignancies and other cancers in patients bearing DDX41m suggests that defects in DDX41 lead to loss of a tumor suppressor function, likely related to activities in RNA splicing and processing pathways. Seventy percent of cancer cases with DDX41m are associated with MDS/AML alone. More than 65% of familial cases harbor heterozygous germline frameshift mutations, of which p.D140Gfs*2 is the most common. A somatic DDX41m of the second allele is acquired in 70% of cases, leading to hematological malignancy. Myeloid neoplasms with DDX41m are typically characterized by long latency, high-risk disease at presentation with normal cytogenetics and without any additional molecular markers. Recent reports suggests that a subgroup of these patients have an indolent clinical course and have a better long-term survival compared to favorable or intermediate risk AML.

Summary

Distinct clinical/pathologic features and favorable outcomes in MDS/AML highlight the need for standardized classification and gene specific guidelines that could assist in management decisions in patients with DDX41m.

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References

  1. Owen C, Barnett M, Fitzgibbon J. Familial myelodysplasia and acute myeloid leukaemia—a review. Br J Haematol. 2008;140:123–32. https://doi.org/10.1111/j.1365-2141.2007.06909.x.

    Article  CAS  PubMed  Google Scholar 

  2. Arber DA, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405. https://doi.org/10.1182/blood-2016-03-643544.

    Article  CAS  PubMed  Google Scholar 

  3. Sébert M, et al. Germline DDX41 mutations define a significant entity within adult MDS/AML patients. Blood. 2019;134:1441–4. https://doi.org/10.1182/blood.2019000909.

    Article  PubMed  Google Scholar 

  4. Maciejewski JP, Padgett RA, Brown AL, Müller-Tidow C. DDX41-related myeloid neoplasia. Semin Hematol. 2017;54:94–7. https://doi.org/10.1053/j.seminhematol.2017.04.007.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Omura H, et al. Structural and functional analysis of DDX41: a bispecific immune receptor for DNA and cyclic dinucleotide. Sci Rep. 2016;6:34756. https://doi.org/10.1038/srep34756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Polprasert C, et al. Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell. 2015;27:658–70. https://doi.org/10.1016/j.ccell.2015.03.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Abou Dalle I, et al. Successful lenalidomide treatment in high risk myelodysplastic syndrome with germline DDX41 mutation. Am J Hematol. 2020;95:227–9. https://doi.org/10.1002/ajh.25610.

    Article  PubMed  Google Scholar 

  8. Wan Z, Han B. Clinical features of DDX41 mutation-related diseases: a systematic review with individual patient data. Ther Adv Hematol. 2021;12:20406207211032430. https://doi.org/10.1177/20406207211032433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Alkhateeb HB, et al. Genetic features and clinical outcomes of patients with isolated and comutated DDX41-mutated myeloid neoplasms. Blood Adv. 2022;6:528–32. https://doi.org/10.1182/bloodadvances.2021005738.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Quesada AE, et al. DDX41 mutations in myeloid neoplasms are associated with male gender, TP53 mutations and high-risk disease. Am J Hematol. 2019;94:757–66. https://doi.org/10.1002/ajh.25486.

    Article  CAS  PubMed  Google Scholar 

  11. Choi EJ, et al. Unique ethnic features of DDX41 mutations in patients with idiopathic cytopenia of undetermined significance, myelodysplastic syndrome, or acute myeloid leukemia. Haematologica. 2022;107:510–8. https://doi.org/10.3324/haematol.2020.270553.

    Article  CAS  PubMed  Google Scholar 

  12. Lewinsohn M, 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. https://doi.org/10.1182/blood-2015-10-676098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ali MAM. DEAD-box RNA helicases: the driving forces behind RNA metabolism at the crossroad of viral replication and antiviral innate immunity. Virus Res. 2021;296: 198352. https://doi.org/10.1016/j.virusres.2021.198352.

    Article  CAS  PubMed  Google Scholar 

  14. Zhang Z, et al. The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat Immunol. 2011;12:959–65. https://doi.org/10.1038/ni.2091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Parvatiyar K, et al. The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response. Nat Immunol. 2012;13:1155. https://doi.org/10.1038/ni.2460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lee KG, et al. Bruton’s tyrosine kinase phosphorylates DDX41 and activates its binding of dsDNA and STING to initiate type 1 interferon response. Cell Rep. 2015;10:1055–65. https://doi.org/10.1016/j.celrep.2015.01.039.

    Article  CAS  PubMed  Google Scholar 

  17. Stavrou S, Blouch K, Kotla S, Bass A, Ross SR. Nucleic acid recognition orchestrates the anti-viral response to retroviruses. Cell Host Microbe. 2015;17:478–88. https://doi.org/10.1016/j.chom.2015.02.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Stavrou, S., Aguilera, A. N., Blouch, K. & Ross, S. R. DDX41 recognizes RNA/DNA retroviral reverse transcripts and is critical for in vivo control of murine leukemia virus infection. mBio (2018) 9, https://doi.org/10.1128/mBio.00923-18.

  19. Weinreb JT, et al. Excessive R-loops trigger an inflammatory cascade leading to increased HSPC production. Dev Cell. 2021;56:627-640.e625. https://doi.org/10.1016/j.devcel.2021.02.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mosler T, et al. R-loop proximity proteomics identifies a role of DDX41 in transcription-associated genomic instability. Nat Commun. 2021;12:7314. https://doi.org/10.1038/s41467-021-27530-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Weinreb JT, Gupta V, Sharvit E, Weil R, Bowman TV. Ddx41 inhibition of DNA damage signaling permits erythroid progenitor expansion in zebrafish. Haematologica. 2022;107:644–54. https://doi.org/10.3324/haematol.2020.257246.

    Article  CAS  PubMed  Google Scholar 

  22. Polprasert C, et al. Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell. 2015;27:658–70. https://doi.org/10.1016/j.ccell.2015.03.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chlon TM, et al. Germline DDX41 mutations cause ineffective hematopoiesis and myelodysplasia. Cell Stem Cell. 2021. https://doi.org/10.1016/j.stem.2021.08.004.

    Article  PubMed  Google Scholar 

  24. Kadono M, et al. Biological implications of somatic DDX41 p.R525H mutation in acute myeloid leukemia. Exp Hematol. 2016;44:745-754.e744. https://doi.org/10.1016/j.exphem.2016.04.017.

    Article  CAS  PubMed  Google Scholar 

  25. Wan Z, Han B. Clinical features of DDX41 mutation-related diseases: a systematic review with individual patient data. Therapeutic Advances in Hematology. 2021;12:20406207211032430. https://doi.org/10.1177/20406207211032433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Choi EJ, et al. Unique ethnic features of DDX41 mutations in patients with idiopathic cytopenia of undetermined significance, myelodysplastic syndrome, or acute myeloid leukemia. Haematologica. 2021. https://doi.org/10.3324/haematol.2020.270553.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Polprasert C, et al. Novel DDX41 variants in Thai patients with myeloid neoplasms. Int J Hematol. 2020;111:241–6. https://doi.org/10.1007/s12185-019-02770-3.

    Article  CAS  PubMed  Google Scholar 

  28. Signer RA, Magee JA, Salic A, Morrison SJ. Haematopoietic stem cells require a highly regulated protein synthesis rate. Nature. 2014;509:49–54. https://doi.org/10.1038/nature13035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chlon TM, et al. Germline DDX41 mutations cause ineffective hematopoiesis and myelodysplasia. Cell Stem Cell. 2021;28:1966-1981.e1966. https://doi.org/10.1016/j.stem.2021.08.004.

    Article  CAS  PubMed  Google Scholar 

  30. Kobayashi S, 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. https://doi.org/10.1038/leu.2017.44.

    Article  CAS  PubMed  Google Scholar 

  31. Gibson CJ, et al. Donor clonal hematopoiesis and recipient outcomes after transplantation. J Clin Oncol. 2021;40:189–201. https://doi.org/10.1200/JCO.21.02286.

    Article  CAS  PubMed  Google Scholar 

  32. Berger G, et al. Re-emergence of acute myeloid leukemia in donor cells following allogeneic transplantation in a family with a germline DDX41 mutation. Leukemia. 2016;31:520. https://doi.org/10.1038/leu.2016.310.

    Article  CAS  PubMed  Google Scholar 

  33. Li P, et al. AML with germline DDX41 variants is a clinicopathologically distinct entity with an indolent clinical course and favorable outcome. Leukemia. 2021. https://doi.org/10.1038/s41375-021-01404-0.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Alkhateeb HB, et al. Genetic features and clinical outcomes of patients with isolated and comutated DDX41-mutated myeloid neoplasms. Blood Adv. 2021. https://doi.org/10.1182/bloodadvances.2021005738.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Negoro E, et al. Molecular predictors of response in patients with myeloid neoplasms treated with lenalidomide. Leukemia. 2016;30:2405–9. https://doi.org/10.1038/leu.2016.228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Madanat YF, et al. Genomic biomarkers predict response/resistance to lenalidomide in non-Del(5q) myelodysplastic syndromes. Blood. 2018;132:1797. https://doi.org/10.1182/blood-2018-99-114681.

    Article  Google Scholar 

  37. Li R, Sobreira N, Witmer PD, Pratz KW, Braunstein EM. Two novel germline DDX41 mutations in a family with inherited myelodysplasia/acute myeloid leukemia. Haematologica. 2016;101:e228-231. https://doi.org/10.3324/haematol.2015.139790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Division of Hematology & Medical Oncology, Mayo Clinic Cancer Center, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Talha Badar

  2. Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, USA

    Timothy Chlon

  3. Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, USA

    Timothy Chlon

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  1. Talha Badar
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Correspondence to Talha Badar or Timothy Chlon.

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This article is part of the Topical Collection on Germline Predisposition to Myeloid Neoplasms.

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Badar, T., Chlon, T. Germline and Somatic Defects in DDX41 and its Impact on Myeloid Neoplasms. Curr Hematol Malig Rep 17, 113–120 (2022). https://doi.org/10.1007/s11899-022-00667-3

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  • DOI: https://doi.org/10.1007/s11899-022-00667-3

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