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

Abstract

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.

• Authors: Jason R Schwartz, Michael P Walsh, Jing Ma, Tamara Lamprecht, Shuoguo Wang, Gang Wu, Susana Raimondi, Brandon M Triplett, Jeffery M Klco
• Journal: Cold Spring Harbor molecular case studies (Cold Spring Harb Mol Case Stud) Vol. 4 Issue 5 (10 2018) ISSN: 2373-2873 [Electronic] United States
• PMID: 29891567 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Schwartz et al.; Published by Cold Spring Harbor Laboratory Press.

Chemical References

• ASXL1 protein, human
• Repressor Proteins

Topics

• Adolescent
• Adult
• Female
• Hematopoietic Stem Cell Transplantation (adverse effects, methods)
• High-Throughput Nucleotide Sequencing (methods)
• Humans
• Leukemia, Myeloid, Acute (genetics, metabolism)
• Male
• Myelodysplastic Syndromes (diagnosis, genetics)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (physiopathology, therapy)
• Repressor Proteins (genetics)
• Tissue Donors
• Transplantation Conditioning (methods)
• Transplantation, Homologous (methods)