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

Cancer Sci. 2019 Oct;110(10):3358-3367. doi: 10.1111/cas.14160. Epub 2019 Sep 10.


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.

Keywords: Down syndrome; acute lymphoblastic leukemia; children; epigenetic analysis; genetic analysis.

MeSH terms

  • Cell Differentiation
  • Child
  • Chromosomes, Human, Pair 21 / genetics
  • Core Binding Factor Alpha 2 Subunit / genetics*
  • DNA Methylation*
  • Down Syndrome / complications*
  • Down Syndrome / genetics
  • Epigenesis, Genetic
  • Female
  • Gene Expression Profiling / methods*
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Philadelphia Chromosome
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Promoter Regions, Genetic
  • Sequence Analysis, DNA
  • Sequence Analysis, RNA


  • Core Binding Factor Alpha 2 Subunit
  • RUNX1 protein, human