Cancer Cell
Volume 36, Issue 2, 12 August 2019, Pages 123-138.e10
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Article
Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome

https://doi.org/10.1016/j.ccell.2019.06.007Get rights and content
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Highlights

  • 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

Summary

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.

Key words

Acute myeloid leukemia
Down syndrome
preleukemia
cancer transformation
CRISPR screen
GATA1

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These authors contributed equally

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