Perspectives on the origin and therapeutic opportunities in Down syndrome-associated leukemia

It is now well accepted that germline or de novo genetic alterations predispose to cancer development, especially during childhood. Among them, constitutive trisomy 21, also known as Down syndrome (DS), has been shown to predispose to acute leukemia affecting both the myeloid (ML-DS) and lymphoid (DS-ALL) lineages. ML-DS is associated with a good prognosis compared to children without DS, due in part to a higher sensitivity to conventional chemotherapy. In contrast, children with DS-ALL have inferior outcomes compared to children without DS, predominantly due to treatment-related toxicity and higher rates of relapse. This discrepancy in outcomes between ML-DS and DS-ALL is mirrored at the biological and molecular level. Indeed, whereas the mechanisms of leukemia initiation, multi-step pathogenesis and progression in response to treatment are well described for ML-DS, they remain mostly elusive for children with DS-ALL. This review will integrate the most recent studies in this field, to better understand this discrepancy and address the knowledge gap for DS-ALL, provide perspectives on the origin and the development of novel therapeutic approaches for DS-associated leukemia, to ultimately improve the quality of care and long-term survival for children with DS.