Journal article
Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome
M Labuhn, K Perkins, S Matzk, L Varghese, C Garnett, E Papaemmanuil, M Metzner, A Kennedy, V Amstislavskiy, T Risch, R Bhayadia, D Samulowski, DC Hernandez, B Stoilova, V Iotchkova, U Oppermann, C Scheer, K Yoshida, A Schwarzer, J Taub Show all
Cancer Cell | Published : 2019
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 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 recu..
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Awarded by CHILDREN with CANCER UK
Funding Acknowledgements
We thank D. Trono of EPFL, Switzerland for pMD2.G (Addgene plasmid 12259) and psPAX2 (Addgene plasmid 12260). The following funding is acknowledged: J.-H.K. by ERC via European Union Horizon 2020 (no. 714226), DFG (KL-2374/1-3), Beat Leukemia with Connor and St. Baldrick's Robert Arceci Innovations Award; D.H. by German Cancer Aid (111743); D.H. and J.-H.K. by DFG (HE-7482/1-1); M.L. by Hannover Biomedical Research School. P.V. and I.R. by Bloodwise Specialist Programme Grant 13001 and Children with Cancer UK, NIHR Oxford Biomedical Research Fund. P.V. by MRC MHU (MC_UU_12009/11); C.G. by Wellcome Trust Clinical Training Fellowship; L.V. by Mouve-in Louvain and Haas-Teichen Postdoctoral Fellowships; S.C. by WelBio F 44/8/5-MCF/UIG. 10955, Action de Recherche Concertee 16/21-073, Salus Sanguinis, Foundation "Les avions de Sebastien," and Fondation Contre le Cancer, Belgium.