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The role of germline mutation profiling in the selection of related donors for haematopoietic stem cell transplantation

Bone Marrow Transplantation volume 55, pages 1502–1505 (2020)Cite this article

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Myeloid neoplasms (MNs) are generally considered somatic diseases. However, the role of genetic predisposition to MNs by the occurrence of germline mutations is being increasingly recognized [1, 2]. While this is relevant for genetic counselling of MN patients and their families, it also impacts MN treatment strategies. This is particularly the case for allogeneic haematopoietic stem cell transplantation (alloHSCT), as the use of related donors with the same predisposing mutation might lead to devastating post-transplant complications [3]. Consequently, comprehensive germline screening of MN predisposition genes in potential related donors by next-generation sequencing (NGS) has recently been suggested in cases where familial occurrence of MNs is suspected [4, 5]. We present two cases of human leucocyte antigen (HLA)-matched sibling alloHSCT for MNs, where donor-derived myelodysplastic syndrome (MDS) and poor graft function, respectively, developed as severe post-transplant complications. In both cases, alloHSCT was inadvertently performed with donors carrying the same germline mutation as the index patient. Importantly, however, both donors were apparently healthy, respective family histories lacked evidence of familial MNs and classical MN predisposition genes were unaffected.

DNA preparation, targeted deep sequencing, whole exome sequencing (WES) and Sanger sequencing have been performed as described previously [6], and as outlined in the supplementary methods, respectively. The study was approved by the ethics committee of the Medical University of Graz, Graz, Austria (vote number 30-464 ex 17/18) and performed in accordance with the Declaration of Helsinki.

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References

  1. 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 

  2. Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373:1136–52.

    Article  Google Scholar 

  3. Babushok DV, Bessler M, Olson TS. Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults. Leuk Lymphoma. 2016;57:520–36.

    Article  CAS  Google Scholar 

  4. Churpek JE, Artz A, Bishop M, Liu H, Godley LA. Correspondence regarding the consensus statement from the Worldwide Network for Blood and Marrow Transplantation Standing Committee on Donor Issues. Biol Blood Marrow Transplant. 2016;22:183–4.

    Article  Google Scholar 

  5. 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;31:520–2.

    Article  CAS  Google Scholar 

  6. Caraffini V, Geiger O, Rosenberger A, Hatzl S, Perfler B, Berg JL, et al. Loss of RAF kinase inhibitor protein is involved in myelomonocytic differentiation and aggravates RAS-driven myeloid leukemogenesis. Haematologica. 2019; https://doi.org/10.3324/haematol.2018.209650.

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

    Article  CAS  Google Scholar 

  8. Hsu AP, Johnson KD, Falcone EL, Sanalkumar R, Sanchez L, Hickstein DD, et al. GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome. Blood. 2013;121:3830–7. S1–7.

    Article  CAS  Google Scholar 

  9. 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;30:1916–20.

    Article  CAS  Google Scholar 

  10. 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;29:2101–4.

    Article  CAS  Google Scholar 

  11. Seiter K, Htun K, Baskind P, Liu Z. Acute myeloid leukemia in a father and son with a germline mutation of ASXL1. Biomark Res. 2018;6:7. 018-0121-3.

    Article  Google Scholar 

  12. Zhang P, Chen Z, Li R, Guo Y, Shi H, Bai J, et al. Loss of ASXL1 in the bone marrow niche dysregulates hematopoietic stem and progenitor cell fates. Cell Discov. 2018;4:4-017-0004-z.

    Google Scholar 

Download references

Acknowledgements

The authors would like to thank all study participants for sample donation. This study was supported by research funding from the Austrian Science Fund (grants P26619-B19 to AZ and P 31430-B26 to HS). Research in the laboratories of AZ, AW and HS is further supported by Leukämiehilfe Steiermark.

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Authors and Affiliations

  1. Division of Haematology, Medical University of Graz, Graz, Austria

    Armin Zebisch, Stefan Hatzl, Barbara Uhl, Sonja Wurm, Albert Wölfler, Hildegard T. Greinix & Heinz Sill

  2. Otto Loewi Research Centre for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria

    Armin Zebisch

  3. Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria

    Gerlinde Winter, Karl Kashofer & Gerald Hoefler

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  1. Armin Zebisch
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Contributions

AZ, GW, SH, BU and SW performed research, AZ, KK, AW, HTG, GH and HS performed data analysis. AZ, SH, BU, SW, AW and HS collected patient specimens. AZ and HS conceived and supervised the study. AZ and HS wrote the paper. All authors read and agreed to the paper.

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Correspondence to Armin Zebisch.

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Zebisch, A., Winter, G., Kashofer, K. et al. The role of germline mutation profiling in the selection of related donors for haematopoietic stem cell transplantation. Bone Marrow Transplant 55, 1502–1505 (2020). https://doi.org/10.1038/s41409-019-0691-1

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