Integrated genetic and epigenetic analysis revealed heterogeneity of acute lymphoblastic leukemia in Down syndrome

Children with Down syndrome (DS) are at a 20‐fold increased risk for acute lymphoblastic leukemia (ALL). Compared to children with ALL and no DS (non‐DS‐ALL), those with DS and ALL (DS‐ALL) harbor uncommon genetic alterations, suggesting DS‐ALL could have distinct biological features. Recent studies have implicated several genes on chromosome 21 in DS‐ALL, but the precise mechanisms predisposing children with DS to ALL remain unknown. Our integrated genetic/epigenetic analysis revealed that DS‐ALL was highly heterogeneous with many subtypes. Although each subtype had genetic/epigenetic profiles similar to those found in non‐DS‐ALL, the subtype distribution differed significantly between groups. The Philadelphia chromosome‐like subtype, a high‐risk B‐cell lineage variant relatively rare among the entire pediatric ALL population, was the most common form in DS‐ALL. Hypermethylation of RUNX1 on chromosome 21 was also found in DS‐ALL, but not non‐DS‐ALL. RUNX1 is essential for differentiation of blood cells, especially B cells; thus, hypermethylation of the RUNX1 promoter in B‐cell precursors might be associated with increased incidence of B‐cell precursor ALL in DS patients.