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Down syndrome and leukemia: insights into leukemogenesis and translational targets
Marion K Mateos1, Draga Barbaric1, Sally-Anne Byatt1
11 Kids Cancer Centre, Sydney Children's Hospital, Randwick, Australia ; 2 School of Women's and Children's Health, University of New South Wales, Kensington, Australia ; 3 Children's Cancer Institute Australia, University of New South Wales, Lowy Cancer Centre, Randwick, Australia.
Insights
Children with Down syndrome (DS) face higher leukemia risks. Research explores pre-leukemia (TMD) and leukemia development, seeking new therapeutic targets for myeloid leukemia of Down syndrome (ML-DS) and DS-ALL.
Area of Science:
- Pediatric Oncology
- Hematology
- Genetics
Background:
- Children with Down syndrome (DS) have a substantially elevated risk of developing childhood leukemia, specifically acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (DS-ALL).
- A common pre-leukemic condition, transient myeloproliferative disorder (TMD), characterized by a GATA1 mutation, occurs in up to 30% of newborns with DS, with a quarter progressing to AMKL or myelodysplastic syndrome (MDS).
- Myeloid leukemia of Down syndrome (ML-DS) encompasses AMKL and MDS in young children with DS and a GATA1 somatic mutation, representing a critical multi-step leukemogenesis process.
Purpose of the Study:
- To review current research on the genetic and epigenetic drivers of ML-DS and DS-ALL.
- To identify potential therapeutic targets for preventing leukemia development in children with DS.
- To explore how new research findings may impact the management of DS, pre-leukemia, and leukemia in affected children.
Main Methods:
- Review of genetic and epigenetic studies related to leukemia in Down syndrome.
- Analysis of mutation data, including GATA1 mutations in TMD and ML-DS.
- Examination of JAK-STAT pathway mutations in DS-ALL.
Main Results:
- Transient myeloproliferative disorder (TMD) in newborns with Down syndrome (DS) is linked to GATA1 mutations and can progress to myeloid leukemia of Down syndrome (ML-DS).
- DS-ALL frequently involves mutations in the JAK-STAT pathway, suggesting potential efficacy of JAK inhibitors.
- Genetic and epigenetic research has identified candidate driver mutations crucial for the development of ML-DS and DS-ALL.
Conclusions:
- Understanding the multi-step leukemogenesis in DS is crucial for identifying preventative therapeutic targets.
- Targeted therapies, such as JAK inhibitors for DS-ALL, show promise for improving outcomes.
- Advances in genetic and epigenetic research are paving the way for improved management strategies for children with DS and associated leukemias.
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.
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