Children with Down syndrome have a more than 100-fold increased risk of developing acute myeloid leukemia before their 5th birthday compared to children without Down syndrome. Their risk of acute lymphoblastic leukemia (ALL) is also increased by around 30-fold. In this lecture, Dr. Irene Roberts will discuss current knowledge about the biologic and molecular basis of this striking relationship between leukemia and Down syndrome, the role of trisomy 21 in leukemogenesis and the clinical implications of these findings. 

Dr. Roberts will focus mainly on Myeloid Leukemia of Down syndrome (ML-DS) which originates in utero and typically presents with a self-limiting, neonatal leukemic syndrome known as Transient Abnormal Myelopoiesis (TAM). TAM is caused by co-operation between trisomy 21-associated abnormalities of fetal hematopoiesis and somatic N-terminal mutations in the transcription factor gene GATA1. Around 10% of all neonates with Down syndrome have clinical signs of TAM although the frequency of hematologically silent GATA1 mutations in neonates with Down syndrome is much higher (~30%). While most cases of TAM/Silent TAM resolve without treatment within 3-4 months, in 10-20% of cases transformation to full-blown leukemia occurs within the first 4 years of life when cells harboring GATA1 mutations persist and acquire secondary mutations, most often in cohesin genes. 

Dr. Roberts will also touch on ALL in Down syndrome which presents after the first few months of life and is characterized by a high frequency of rearrangement of the CRLF2 gene often co-occurring with activating mutations in JAK2 or RAS genes. While treatment of ML-DS achieves long-term survival in ~90% of children, outcome of DS-ALL is inferior to ALL in children without Down syndrome. Ongoing studies in primary cells and model systems indicate that the role of trisomy 21 in Down syndrome leukemogenesis is complex and cell context-dependent but also show promise in developing new approaches to management, including treatment of relapse where outcome of both ML-DS and DS-ALL remains poor.