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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.

Original publication




Journal article


Cancer Cell

Publication Date





123 - 138.e10


Acute myeloid leukemia, CRISPR screen, Down syndrome, GATA1, cancer transformation, preleukemia, Animals, Biomarkers, Tumor, Cell Transformation, Neoplastic, Chromosomes, Human, Pair 21, Cytokine Receptor Common beta Subunit, Disease Models, Animal, Disease Progression, Down Syndrome, GATA1 Transcription Factor, Gene Expression Regulation, Leukemic, Genetic Predisposition to Disease, HEK293 Cells, Humans, Leukemia, Myeloid, Leukemoid Reaction, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Transgenic, Mutation, Phenotype, Transcription, Genetic