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Letters to the Editor
ated with an increased risk of developing DCMN.14 Interestingly, CHIP-associated mutations were not found in any of the donors in our cohort, even though 5 of 7 were over 55 years old. This observation indicates that dif- ferent mechanisms may be involved in the development of DCMN which would need further investigation.
Genetic predisposing factors are presumed to play an important role in the development of MN. Likewise, 16- 21% of cancer survivors who developed t-MN have a germline mutation associated with inherited cancer sus- ceptibility genes.15 It could be that individuals with germline mutations in these genes are particularly suscep- tible to cytotoxic chemotherapy and/or radiation.
The growing use of next-generation sequencing (NGS) to study gene panels to define patient prognosis or identify targetable genomic alterations would allow detection of germline variants with clinical significance in tumor sam- ples. Identification of germline mutations in the recipient could rule out the variant in family members. Relatives with the mutation would not be considered as donors and would eventually be referred for genetic counseling.
In most cases reported in the literature, the donor has no evidence of MN development.2 Indeed, donors with such inherited molecular alterations do not necessarily develop leukemia, and they can live for many years without evi- dence of the disease, since other genetic or environmental factors, which are usually altered in transplanted patients, might play an important role in the development of malig- nant disease.
Presumably not just one mechanism from among those mentioned above is responsible for the leukemic transfor- mation in donor cells. But a combination of various condi- tions would contribute to the development of DCMN after allo-HSCT. Such pre-leukemic stem cells from the donor might increase the likelihood that, later, co-operat- ing mutations arise in cells that already contain the initiat- ing mutations in a context of decreased immune surveil- lance. The relative contribution of each of the genetic and transplant-related factors to donor-derived leukemia is still not known. Novel approaches based on in-depth NGS to study consecutive samples from the post-transplant period in these patients appear promising to discover new genes involved in the development of MN and to decipher the ultimate mechanisms of leukemogenesis.
Julia Suárez-González,1,2 Juan Carlos Triviño,3 Guiomar Bautista,4 José Antonio García-Marco,4
Ángela Figuera,5 Antonio Balas,6 José Luis Vicario,6 Francisco José Ortuño,7 Raúl Teruel,7 José María Álamo,8 Diego Carbonell,2,9 Cristina Andrés-Zayas,1,2
Nieves Dorado,2,9 Gabriela Rodríguez-Macías,9 Mi Kwon,2,9 José Luis Díez-Martín,2,9,10 Carolina Martínez-Laperche2,9* and Ismael Buño1,2,9,11* on behalf of the Spanish Group for Hematopoietic Transplantation (GETH)
1Genomics Unit, Gregorio Marañón General University Hospital, Gregorio Marañón Health Research Institute (IiSGM), Madrid; 2Gregorio Marañón Health Research Institute (IiSGM), Madrid; 3Sistemas Genómicos, Valencia; 4Department of Hematology, Puerta de Hierro General University Hospital, Madrid; 5Department of Hematology, La Princesa University Hospital, Madrid; 6Department of Histocompatibility, Madrid Blood Centre, Madrid; 7Department of Hematology and Medical Oncology Unit, IMIB-Arrixaca, Morales Meseguer General University Hospital, Murcia; 8Centro Inmunológico de Alicante - CIALAB, Alicante; 9Department of Hematology, Gregorio Marañón General University Hospital, Madrid; 10Department of Medicine, School of Medicine, Complutense University of Madrid, Madrid and 11Department of Cell Biology, School of Medicine, Complutense University of Madrid, Madrid, Spain
*CM-L and IB contributed equally as co-senior authors.
Correspondence:
ISMAEL BUÑO - ismaelbuno@iisgm.es
doi:10.3324/haematol.2019.234609
Funding: the present work was partially supported by the Ministry of Economy and Competitiveness ISCIII-FIS grants PI17/1880, co- financed by ERDF (FEDER) Funds from the European Commission, “A way of making Europe”, as well as grants from the Asociación Madrileña de Hematología y Hemoterapia (AMHH), Asociación Española Contra el Cáncer (AECC) and Fundación Mutua Madrileña (FMM).
Acknowledgments: the authors are grateful to the patients and their families, as well as to the staff at Gregorio Marañón General University Hospital, Gregorio Marañón Health Research Institute,
La Princesa University Hospital, Puerta de Hierro University Hospital, Transfusion Centre of the Community of Madrid, Morales Meseguer General University Hospital and Spanish Group of Hematopoietic Transplantation (GETH). The authors wish to thank the biobanks at Puerta de Hierro University Hospital and Puerta de Hierro Health Research Institute (IDIPHIM) for some of the human specimens used in this study.
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