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 and Ruben van Boxtel

Blood Cancer Discov August 5 2021 DOI: 10.1158/2643-3230.BCD-21-0010

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 (HSPC), 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 patients with pAML. Compared with normal HSPCs, a subset of pAML cases harbored more somatic mutations and a distinct composition of mutational process signatures. We hypothesize that these cases might have arisen from a more committed progenitor. This subset had better outcomes than pAML cases with mutation burden comparable with age-matched healthy HSPCs. Our study provides insights into the etiology and patient stratification of pAML.

Significance: Genome-wide analysis of pAML and patient-matched HSPCs provides new insights into the etiology of the disease and shows the clinical potential of these analyses for patient stratification.