1. Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome
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Yasuhide Hayashi, Jan-Henning Klusmann, M Labuhn, Udo Oppermann, Alison Kennedy, Sören Matzk, David Samulowski, Marie-Laure Yaspo, Takashi Taga, Irene Roberts, Raj Bhayadia, C Scheer, Leila N. Varghese, Mitchell J. Weiss, Dirk Heckl, Kelly J. Perkins, Thomas Risch, Vyacheslav Amstislavskiy, John D. Crispino, Etsuro Ito, Peter J. Campbell, Seishi Ogawa, Jeffrey W. Taub, Bilyana Stoilova, Stefan N. Constantinescu, Adrian Schwarzer, Dirk Reinhardt, Paresh Vyas, Kenichi Yoshida, Elli Papaemmanuil, Marlen Metzner, Valentina Iotchkova, Catherine Garnett, David Cruz Hernandez, UCL - SSS/DDUV/SIGN - Cell signalling, and UCL - (SLuc) Service d'hématologie
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0301 basic medicine ,Cancer Research ,Myeloid ,Transcription, Genetic ,Chromosomes, Human, Pair 21 ,Down syndrome ,Preleukemia ,Medizin ,cancer transformation ,preleukemia ,CRISPR screen ,Cytokine Receptor Common beta Subunit ,0302 clinical medicine ,Mice, Inbred NOD ,GATA1 Transcription Factor ,Exome ,Gene Expression Regulation, Leukemic ,Myeloid leukemia ,GATA1 ,3. Good health ,medicine.anatomical_structure ,Cell Transformation, Neoplastic ,Phenotype ,Oncology ,Leukemia, Myeloid ,030220 oncology & carcinogenesis ,Disease Progression ,Cytokine receptor ,Mice, Transgenic ,Biology ,Article ,Leukemoid Reaction ,03 medical and health sciences ,stomatognathic system ,medicine ,Biomarkers, Tumor ,Animals ,Humans ,Genetic Predisposition to Disease ,Acute myeloid leukemia ,business.industry ,Cell Biology ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,HEK293 Cells ,Cancer cell ,Mutation ,Cancer research ,Down Syndrome ,business ,Trisomy ,030215 immunology - Abstract
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.
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