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Abstract:
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 hot-
spot 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
