Journal
CANCER CELL
Volume 36, Issue 2, Pages 123-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2019.06.007
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Funding
- ERC via European Union [714226]
- DFG [KL-2374/1-3, HE-7482/1-1]
- Beat Leukemia with Connor
- St. Baldrick's Robert Arceci Innovations Award
- German Cancer Aid [111743]
- Hannover Biomedical Research School
- Bloodwise Specialist Programme Grant [13001]
- Children with Cancer UK
- NIHR Oxford Biomedical Research Fund
- MRC MHU [MC_UU_12009/11]
- Wellcome Trust
- Mouve-in Louvain Postdoctoral Fellowship
- Haas-Teichen Postdoctoral Fellowship
- WelBio [F 44/8/5-MCF/UIG. 10955]
- Action de Recherche Concertee [16/21-073]
- Salus Sanguinis
- Foundation Les avions de Sebastien
- Fondation Contre le Cancer, Belgium
- MRC [MC_UU_00016/11, MC_UU_12009/11, MC_U137961146, G1000729] Funding Source: UKRI
- European Research Council (ERC) [714226] Funding Source: European Research Council (ERC)
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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.
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