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Early detection and evolution of pre-leukemic clones in therapy-related myeloid neoplasms following autologous SCT

Gerbrig Berger, Leonie I. Kroeze, Theresia N. Koorenhof-Scheele, Aniek O. de Graaf, Kenichi Yoshida, Hiroo Ueno, Yuichi Shiraishi, Satoru Miyano, Eva van den Berg, Hein Schepers, Bert A. van der Reijden, Seishi Ogawa, Edo Vellenga and Joop H. Jansen

Key points

  • tMNs following ASCT originate from HSCs bearing pre-tMN mutations that are present years before disease onset.

  • Post-ASCT treatment can influence selection and outgrowth of (pre)leukemic clones.

Abstract

Therapy-related myeloid neoplasms (tMNs) are severe adverse events that can occur following treatment with autologous hematopoietic stem cell transplantation (ASCT). This study aimed to investigate the development of tMN following ASCT at the molecular level by whole exome sequencing (WES) and targeted deep sequencing (TDS) in sequential (pre-) tMN samples. WES identified a significantly higher number of mutations in tMN as compared to de novo MDS (median 27 vs 12, p=0.001). The mutations found in tMN did not carry a clear ageing-signature, unlike the mutations found in de novo MDS, indicating a different mutational mechanism. In some patients, tMN mutations were identified in both myeloid and T-cells, suggesting that tMNs may originate from early hematopoietic stem cells (HSCs). However, the mutational spectra of tMN and the preceding malignancies did not overlap, excluding common ancestry for these malignancies. Using TDS, tMN mutations were identified at low variant allele frequencies (VAFs) in transplant material in 70% of the tMN cases. Reconstruction of clonal patterns based on VAFs, revealed that pre-malignant clones can be present more than seven years preceding tMN diagnosis, a finding that was confirmed by immunohistochemistry on bone marrow biopsies. Our results indicate that tMN development following ASCT originates in HSCs bearing tMN mutations that are present years before disease onset and that post-ASCT treatment can influence the selection of these clones. Early detection of pre-malignant clones and monitoring their evolutionary trajectory may help to predict the development of tMN and guide early intervention in the future.

  • Submitted September 11, 2017.
  • Accepted December 27, 2017.