Down syndrome and leukemia: from basic mechanisms to clinical advances

Abstract

Children with Down syndrome (DS, trisomy 21) are at a significantly higher risk of developing acute leukemia compared to the overall population. Many studies investigating the link between trisomy 21 and leukemia initiation and progression have been conducted over the last two decades. Despite improved treatment regimens and significant progress in iden - tifying genes on chromosome 21 and the mechanisms by which they drive leukemogenesis, there is still much that is unknown. A focused group of scientists and clinicians with expertise in leukemia and DS met in October 2022 at the Jérôme Lejeune Foundation in Paris, France for the 1st International Symposium on Down Syndrome and Leukemia. This meeting was held to discuss the most recent advances in treatment regimens and the biology underlying the initiation, progression, and relapse of acute lymphoblastic leukemia and acute myeloid leukemia in children with DS. This review provides a summary of what is known in the field, challenges in the management of DS patients with leukemia, and key questions in the field.

Figure 1.

Overview of Down syndrome-associated leukemia. Trisomy 21 affects fetal blood formation, causing an increase in hematopoietic stem cells and megakaryocyte-erythroid progenitors, but a decrease in B-cell progenitors. Mutations in GATA1 cause transient abnormal myelopoiesis, which can lead to myeloid leukemia of Down syndrome (ML-DS) upon acquisition of additional somatic mutations. In the lymphoid branch, alterations in CRLF2 or JAK2 can lead to Down syndrome-associated acute lymphoblastic leukemia (DS-ALL). In both ML-DS and DS-ALL, the increased dosage of genes located on chromosome 21 cooperates with somatic mutations in disease onset and progression. Figure generated with BioRender.com. HSC: hematopoietic stem cells; MEP: megakaryocyte-erythroid progenitors; chr 21: chromosome 21.