Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome

Abstract

Children with Down syndrome (DS) show a spectrum of clinical anomalies, including cognitive impairment, cardiac malformations, and craniofacial dysmorphy. Moreover, hematologists have also noted that these children commonly show macrocytosis, abnormal platelet counts, and an increased incidence of transient myeloproliferative disease (TMD), acute megakaryocytic leukemia (AMKL), and acute lymphoid leukemia (ALL). In this review, we summarize the clinical manifestations and characteristics of these leukemias, provide an update on therapeutic strategies and patient outcomes, and discuss the most recent advances in DS-leukemia research. With the increased knowledge of the way in which trisomy 21 affects hematopoiesis and the specific genetic mutations that are found in DS-associated leukemias, we are well on our way toward designing improved strategies for treating both myeloid and lymphoid malignancies in this high-risk population.

Figure 1

Diagram of Hsa21 and the regions of trisomy in the various mouse models of DS. Human chromosome 21 and specific genes that may contribute to the development of leukemia in children with DS are shown on the left. Syntenic regions on Mmu16, and the mouse models in which they exist in 3 copies, are depicted on the right. Note that the Tc1 mouse is trisomic for the majority of human chromosome 21. Mouse models outlined in red are discussed under “Utility of animal models of DS.”

Figure 2

Hypotheses to explain the pathogenesis of ALL in DS. (A) Constitutional trisomy 21 may enhance proliferation or survival of preleukemic lymphoid progenitors. An additional specific genetic event, such as a JAK2 mutation or additional chromosome X, cooperates with trisomy 21 to induce leukemia. This model is similar to the cooperation with GATA1 mutations in DS myeloid disorders. (B) The unique microenvironment in children with DS, caused by the presence of trisomy 21 in all body cells, results in an increased risk for usual childhood leukemogenic genetic events, such as TEL/AML1 and hyperdiploidy, and an increase in the common subtypes of childhood ALL. These 2 hypotheses are not mutually exclusive. Note that the latter model is speculative, but is presented as a hypothetical possibility to stimulate discussion and research in this area.