Down syndrome and leukemia: insights into leukemogenesis and translational targets

Abstract

Children with Down syndrome (DS) have a significantly increased risk of childhood leukemia, in particular acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (DS-ALL). A pre-leukemia, called transient myeloproliferative disorder (TMD), characterised by a GATA binding protein 1 (GATA1) mutation, affects up to 30% of newborns with DS. In most cases, the pre-leukemia regresses spontaneously, however one-quarter of these children will go on to develop AMKL or myelodysplastic syndrome (MDS) . AMKL and MDS occurring in young children with DS and a GATA1 somatic mutation are collectively termed myeloid leukemia of Down syndrome (ML-DS). This model represents an important multi-step process of leukemogenesis, and further study is required to identify therapeutic targets to potentially prevent development of leukemia. DS-ALL is a high-risk leukemia and mutations in the JAK-STAT pathway are frequently observed. JAK inhibitors may improve outcome for this type of leukemia. Genetic and epigenetic studies have revealed likely candidate drivers involved in development of ML-DS and DS-ALL. Overall this review aims to identify potential impacts of new research on how we manage children with DS, pre-leukemia and leukemia.

Keywords: (3-5)-MeSH headings; Down syndrome (DS); children; leukemia; preleukemia; transient myeloproliferative disorder (TMD) of Down syndrome.

Figure 1

Myeloid and lymphoid stem cells. This figure describes in a simplified manner the broad division between myeloid and lymphoid lineages. A multipotent hematopoietic stem cell gives rise to a common myeloid progenitor, termed “myeloid stem cell” above; and a common lymphoid progenitor, termed “lymphoid stem cell”. Of relevance to Down syndrome (DS), megakaryoblasts are derived from a myeloid stem cell. Transient myeloproliferative disorder (TMD), a pre-leukemia, and myeloid leukemia of Down syndrome (ML-DS) are both disorders that are due to abnormal megakaryoblasts. Lymphoblasts, seen in DS-acute lymphoblastic leukemia (DS-ALL) are derived from a lymphoid stem cell.

Figure 2

Natural history of TMD in children with Down syndrome (DS) and newly described diagnostic categories. The current incidence of DS is 1/700 to 1/1000 live births. Children who have blasts in the peripheral blood and GATA1 gene mutation detected by conventional methods (Sanger Sequencing/Denaturing High Performance Liquid Chromatography) are termed “TMD” in our diagram above. Based on new findings (14), there is a subgroup of newborns with DS who do not have GATA1 gene mutation detected by conventional methods, but who have a detectable GATA1 gene mutation by next-generation sequencing. The proposed nomenclature for this group is “silent TAM” (14) or “silent TMD”. The incidence of newborn DS with detectable GATA1 gene mutation by conventional methods (“TMD”) is up to 10%. The incidence of “silent TMD” could be up to 20% of newborns with DS. Approximately 20-30% of newborns with TMD will go on to develop ML-DS (myeloid leukemia of Down syndrome). The incidence of ML-DS in children with “silent TMD” or no prior TMD is unknown. ML-DS typically responds very well to chemotherapy. The event-free survival is approximately 80% for ML-DS.

Figure 3

Schematic of “hits” involved in myeloid leukemogenesis in Down syndrome (DS). The first “hit”, or genetic change, is trisomy 21. This occurs prenatally in the fetal liver, which is the site of definitive fetal hematopoiesis. The second hit is GATA1 gene mutation. Transient myeloproliferative disorder (TMD) occurs as a result of the combination of trisomy 21 and GATA1 mutation effects on megakaryocyte progenitors (MKPs). TMD may resolve spontaneously, or less commonly after use of low-dose chemotherapy, in approximately 85% of cases. In order to develop myeloid leukemia of Down syndrome (ML-DS), it is likely that a TMD clone persists due to an additional “hit”; and that this TMD clone is subject to further genetic and/or epigenetic leukemic drivers.