Myeloid leukemia in Down syndrome

Abstract

Although adults with Down syndrome (DS) show a decreased incidence of cancer compared to individuals without DS, children with DS are at an increased risk of leukemia. Nearly half of these childhood leukemias are classified as acute megakaryoblastic leukemia (AMKL), a relatively rare subtype of acute myeloid leukemia (AML). Here, we summarize the clinical features of myeloid leukemia in DS, review recent research on the mechanisms of leukemogenesis, including the roles of GATA1 mutations and trisomy 21, and discuss treatment strategies. Given that trisomy 21 is a relatively common event in hematologic malignancies, greater knowledge of how the genes on chromosome 21 contribute to DS-AMKL will increase our understanding of a broader class of patients with leukemia.

Figure 1. Diagram of Hsa21 and the regions of trisomy in the various mouse models of DS

A) Human chromosome 21 and specific genes in the DS critical region (DSCR) that may contribute to the development of leukemia are shown. The syntenic murine Mmu16 with varying degrees of trisomic representation in the different mouse models is depicted on the right. B) Summary of the hematopoietic phenotype of the murine models and the effect of coexpression of GATA-1s.

Figure 2. Multi-step model of leukemogenesis in Down syndrome

A) Sequential acquisition of known genetic abnormalities and their role in the evolution of DS-AMKL. B) Aberrant signaling pathways implicated in the pathogenesis of DS-AMKL. The chromosome 21 specific genes that appear to have a functional impact in these pathways are highlighted in blue.