Journal article

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

Maurice Labuhn, Kelly Perkins, Soeren Matzk, Leila Varghese, Catherine Garnett, Elli Papaemmanuil, Marlen Metzner, Alison Kennedy, Vyacheslav Amstislayskiy, Thomas Risch, Raj Bhayadia, David Samulowski, David Cruz Hernandez, Bilyana Stoilova, Valentina Lotchkova, Udo Oppermann, Carina Scheer, Kenichi Yoshida, Adrian Schwarzer, Jeffrey Taub Show all

Cancer Cell | CELL PRESS | 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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University of Melbourne Researchers

Grants

Awarded by ERC via European Union


Awarded by DFG


Awarded by German Cancer Aid


Awarded by Bloodwise Specialist Programme Grant


Awarded by MRC MHU


Awarded by WelBio


Awarded by Action de Recherche Concertee


Awarded by NATIONAL CANCER INSTITUTE


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.