Genomics of pediatric acute myeloid leukemia—Novel pediatric-specific subtypes

Abstract

Despite improving clinical outcomes of pediatric acute lymphoblastic leukemia (ALL), those of pediatric acute myeloid leukemia (AML) remain around 70%. This is partly due to a lack of understanding of the genetic background of pediatric AML, appropriate risk stratification, or molecule-targeted therapies. To fill the knowledge gap, we integrated transcriptional and genetic analyses of a large cohort of pediatric AML, identifying two pediatric AML-specific alterations, tandem duplications of UBTF (UBTF-TD) and GDXY insertions of CBFB (CBFB-GDXY), which were mutually exclusive with other class-defining alterations. UBTF-TDs are associated with FLT3-ITD and WT1 mutations, HOXB expression, and poor prognosis, while CBFB-GDXYs were associated with CBF-AML-like expression patterns. These data suggest that these alterations define new molecular subtypes of pediatric AML.

These alterations, as well as other pediatric-specific alterations such as CBFA2A3::GLIS2 or PICALM::MLLT10, are not covered by the current WHO classifications (WHO^5th), resulting in 30% of pediatric AML categorized as “acute myeloid leukemia with other defined genetic alterations” or “acute myeloid leukemia, myelodysplasia-related”. We then systematically categorized 889 pediatric AMLs into 23 molecular categories that are mutually distinct from one another, covering 91.4% of the cohort. These molecular categories were associated with clinical outcomes using two independent cohorts, establishing a prognostic framework based on molecular categories and minimal residual disease. Together, these studies provide the basis for future classification of pediatric AML and treatment strategies.