Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome.

Myeloid leukemia in Down syndrome (ML-DS) clonally evolves from transient abnormal myelopoiesis (TAM), a preleukemic condition in DS newborns. To define mechanisms of leukemic transformation, we combined exome and targeted resequencing of 111 TAM and 141 ML-DS samples with functional analyses. TAM requires trisomy 21 and truncating mutations in GATA1 ; additional TAM variants are usually not pathogenic. By contrast, in ML-DS, clonal and subclonal variants are functionally required. We identified a recurrent and oncogenic hotspot gain-of-function mutation in myeloid cytokine receptor CSF2RB. By a multiplex CRISPR/Cas9 screen in an in vivo murine TAM model, we tested loss-of-function of 22 recurrently mutated ML-DS genes. Loss of 18 different genes produced leukemias that phenotypically, genetically, and transcriptionally mirrored ML-DS. • Genetic and functional analyses of myeloid preleukemia and leukemia in Down syndrome • Non-GATA1 preleukemic mutations are often not required for preleukemia • Previously undescribed transforming hotspot mutation in CSF2RB identified • Loss of function of 18 genes validated in transformation of preleukemia to leukemia Myeloid leukemia in Down syndrome (ML-DS) evolves from transient abnormal myelopoiesis (TAM). Labuhn et al. show that trisomy 21 and GATA1 mutations are sufficient for the development of TAM. They further identify and functionally validate additional variants that drive TAM to ML-DS transformation. [ABSTRACT FROM AUTHOR]