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Clonal dynamics of donor-derived myelodysplastic syndrome after unrelated hematopoietic cell transplantation for high-risk pediatric B-lymphoblastic leukemia

Donor-derived hematologic malignancies are rare complications of hematopoietic cell transplantation (HCT). Although these are commonly either a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), in general, they are a heterogeneous group of diseases, and a unified mechanism for their de...

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Detalles Bibliográficos
Autores principales: Schwartz, Jason R., Walsh, Michael P., Ma, Jing, Lamprecht, Tamara, Wang, Shuoguo, Wu, Gang, Raimondi, Susana, Triplett, Brandon M., Klco, Jeffery M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169831/
https://www.ncbi.nlm.nih.gov/pubmed/29891567
http://dx.doi.org/10.1101/mcs.a002980
Descripción
Sumario:Donor-derived hematologic malignancies are rare complications of hematopoietic cell transplantation (HCT). Although these are commonly either a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), in general, they are a heterogeneous group of diseases, and a unified mechanism for their development has remained elusive. Here we report next-generation sequencing, including whole-exome sequencing (WES), whole-genome sequencing (WGS), and targeted sequencing, of a case of donor-derived MDS (dMDS) following HCT for high-risk B-lymphoblastic leukemia (B-ALL) in an adolescent. Through interrogation of single-nucleotide polymorphisms (SNPs) in the WGS data, we unequivocally prove that the MDS is donor-derived. Additionally, we sequenced 15 samples from 12 time points, including the initial B-ALL diagnostic sample through several post-HCT remission samples, the dMDS, and representative germline samples from both patient and donor, to show that the MDS-related pathologic mutations, including a canonical ASXL1 (p.Y700*) mutation, were detectable nearly 3 yr prior to the morphological detection of MDS. Furthermore, these MDS mutations were not detectable immediately following, and for >1 yr post-, HCT. These data support the clinical utility of comprehensive sequencing following HCT to detect donor-derived malignancies, while providing insights into the clonal progression of dMDS over a 4-yr period.