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

Labuhn, Maurice; Perkins, Kelly; Matzk, Sören; Varghese, Leila; Garnett, Catherine; Papaemmanuil, Elli; Metzner, Marlen; Kennedy, Alison; Amstislavskiy, Vyacheslav; Risch, Thomas; Bhayadia, Raj; Samulowski, David; Hernandez, David Cruz; Stoilova, Bilyana ...; Yaspo, Marie-Laure; Campbell, Peter J.; Roberts, Irene; Constantinescu, Stefan N.; Vyas, Paresh; Heckl, Dirk; Klusmann, Jan-Henning

doi:10.1016/j.ccell.2019.06.007

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

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Matzk, Sören
Gene Regulation and Systems Biology of Cancer (Marie-Laure Yaspo), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Amstislavskiy, Vyacheslav
Gene Regulation and Systems Biology of Cancer (Marie-Laure Yaspo), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Risch, Thomas
Gene Regulation and Systems Biology of Cancer (Marie-Laure Yaspo), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Yaspo, Marie-Laure
Gene Regulation and Systems Biology of Cancer (Marie-Laure Yaspo), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Labuhn, M., Perkins, K., Matzk, S., Varghese, L., Garnett, C., Papaemmanuil, E., et al. (2019). Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome. Cancer Cell, 36(2), 123-138. doi:10.1016/j.ccell.2019.06.007.

Cite as: https://hdl.handle.net/21.11116/0000-0010-0B4E-C

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