Deep genomic characterization highlights complexities and prognostic markers of pediatric acute myeloid leukemia

Abstract

Pediatric acute myeloid leukemia (AML) is an uncommon but aggressive hematological malignancy. The poor outcome is attributed to inadequate prognostic classification and limited treatment options. A thorough understanding on the genetic basis of pediatric AML is important for the development of effective approaches to improve outcomes. Here, by comprehensively profiling fusion genes as well as mutations and copy number changes of 141 myeloid-related genes in 147 pediatric AML patients with subsequent variant functional characterization, we unveil complex mutational patterns of biological relevance and disease mechanisms including MYC deregulation. Also, our findings highlight TP53 alterations as strong adverse prognostic markers in pediatric AML and suggest the core spindle checkpoint kinase BUB1B as a selective dependency in this aggressive subgroup. Collectively, our present study provides detailed genomic characterization revealing not only complexities and mechanistic insights into pediatric AML but also significant risk stratification and therapeutic strategies to tackle the disease.

Insights into the Clinical, Biological and Therapeutic Impact of Copy Number Alteration in Cancer

“…Other less frequent constitutional aneuploidies affecting autosomes such as trisomy 13 and trisomy 18 have also been shown to have an increased incidence of cancer; however, their prognostic value is not known due to the rarity of these CNV-driven cancers [133][134][135]. Constitutional trisomy 8 mosaicism has been shown to predispose to myeloid leukaemia in individual cases [136], which may correlate with somatic +8 being observed in 10-15% of AML cases [81,83].…”