Down syndrome and leukemia: An insight into the disease biology and current treatment options.

Children with Down syndrome (DS) have a 10- to 20-fold greater predisposition to develop acute leukemia compared to the general population, with a skew towards myeloid leukemia (ML-DS). While ML-DS is known to be a subtype with good outcome, patients who relapse face a dismal prognosis. Acute lymphocytic leukemia in DS (DS-ALL) is considered to have poor prognosis. The relapse rate is high in DS-ALL compared to their non-DS counterparts. We have a better understanding about the mutational spectrum of DS leukemia. Studies using animal, embryonic stem cell- and induced pluripotent stem cell-based models have shed light on the mechanism by which these mutations contribute to disease initiation and progression. In this review, we list the currently available treatment strategies for DS-leukemias along with their outcome with emphasis on challenges with chemotherapy-related toxicities in children with DS. We focus on the mechanisms of initiation and progression of leukemia in children with DS and highlight the novel molecular targets with greater success in preclinical trials that have the potential to progress to the clinic.

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

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.