Mutation signatures of pediatric acute myeloid leukemia and normal blood progenitors associated with differential patient outcomes

Arianne M Brandsma, Eline J M Bertrums, Markus J van Roosmalen, Damon A Hofman, Rurika Oka, Mark Verheul, Freek Manders, Joske Ubels, Mirjam E Belderbos, Ruben van Boxtel

Research output: Contribution to journalArticlepeer-review

Abstract

Acquisition of oncogenic mutations with age is believed to be rate limiting for carcinogenesis. However, the incidence of leukemia in children is higher than in young adults. Here we compare somatic mutations across pediatric acute myeloid leukemia (pAML) patient-matched leukemic blasts and hematopoietic stem and progenitor cells (HSPCs), as well as HSPCs from age-matched healthy donors. HSPCs in the leukemic bone marrow have limited genetic relatedness and share few somatic mutations with the cell-of-origin of the malignant blasts, suggesting polyclonal hematopoiesis in pAML patients. Compared to normal HSPCs, a subset of pAML cases harbored more somatic mutations and a distinct composition of mutational process signatures. We hypothesize these cases might have arisen from a more committed progenitor. This subset had better outcomes than pAML cases with mutation burden comparable to age-matched healthy HSPCs. Our study provides insights into the etiology and patient stratification of pAML.

Original languageEnglish
Pages (from-to)484-499
Number of pages16
JournalBlood cancer discovery
Volume2
Issue number5
DOIs
Publication statusPublished - Sept 2021

Keywords

  • Bone Marrow/pathology
  • Child
  • Hematopoiesis
  • Hematopoietic Stem Cells/pathology
  • Humans
  • Leukemia, Myeloid, Acute/genetics
  • Mutation
  • Young Adult

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