Increased risk of leukaemia in children with Down syndrome: a somatic evolutionary view

Abstract

Children show a higher incidence of leukaemia compared with young adolescents, yet their cells are less damaged because of their young age. Children with Down syndrome (DS) have an even higher risk of developing leukaemia during the first years of life. The presence of a constitutive trisomy of chromosome 21 (T21) in DS acts as a genetic driver for leukaemia development, however, additional oncogenic mutations are required. Therefore, T21 provides the opportunity to better understand leukaemogenesis in children. Here, we describe the increased risk of leukaemia in DS during childhood from a somatic evolutionary view. According to this idea, cancer is caused by a variation in inheritable phenotypes within cell populations that are subjected to selective forces within the tissue context. We propose a model in which the increased risk of leukaemia in DS children derives from higher rates of mutation accumulation, already present during fetal development, which is further enhanced by changes in selection dynamics within the fetal liver niche. This model could possibly be used to understand the rate-limiting steps of leukaemogenesis early in life.

Keywords: DS-ALL; Down syndrome; ML-DS; TAM; paediatric leukaemia; somatic evolutionary model.

Fig. 1.

GATA1 aberrations in transient abnormal myelopoiesis (TAM). Analysis of all GATA1 mutations identified in TAM, which are annotated in the Catalogue of Somatic Mutations in Cancer (COSMIC) Cancer Gene Census database and GATA1 mutations from the recently published study of Labuhn et al. (Refs , , , , , –149). (a) Pie chart showing the different types of GATA1 mutations observed in TAM (pre)leukaemic blasts. (b) 96-trinucleotide spectrum of all single nucleotide variants (SNVs) observed in GATA1. (c) The spectrum of insertions and deletions (indels) within GATA1.

Fig. 2.

Development of transient abnormal myelopoiesis (TAM) and myeloid leukaemia of Down syndrome (ML-DS). Model for the development of TAM and ML-DS in Down syndrome individuals. Schematic representation, indicating the initiation of TAM before birth when trisomy 21 (T21) fetal haematopoietic stem and progenitor cells (HSPCs) acquire a GATA1 mutation. The proliferation of (pre)leukaemic TAM blasts in the fetal liver is supported by secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with increased insulin growth factor-2 (IGF) signalling and lower levels of IFN signalling. TAM resolves when haematopoiesis migrates to the bone marrow after birth and interferon (IFN) signalling increases. Additional oncogenic mutations in an existing GATA1 mutated clone provide these cells with an additional growth advantage and are required for progression towards ML-DS.

Fig. 3.

Development of DS acute lymphoblastic leukemia (DS-ALL). Model for the development of acute lymphoblastic leukemia (ALL) in Down syndrome individuals. Trisomy 21 (T21) haematopoietic stem and progenitor cells (HSPCs) show a B-cell maturation defect. An extra copy of genes encoding chromatin modifiers on chromosome 21 causes a decrease in H3k27me3 marks and an increase in H3K27ac and H3K4me3 marks on genes involved in B-cell proliferation and B-ALL development, which will result in overexpression of these genes. The acquisition of cancer driver mutations and additional oncogenic mutations is sufficient for the development of DS-ALL.