Maurice Labuhn, Kelly Perkins, Sören Matzk, Leila Varghese, Catherine Garnett, Elli Papaemmanuil, Marlen Metzner, Alison Kennedy, Vyacheslav Amstislavskiy, Thomas Risch, Raj Bhayadia, David Samulowski, David Cruz Hernandez, Bilyana Stoilova, Valentina Iotchkova, Udo Oppermann, Carina Scheer, Kenichi Yoshida, Adrian Schwarzer, Jeffrey W Taub, John D Crispino, Mitchell J Weiss, Yasuhide Hayashi, Takashi Taga, Etsuro Ito, Seishi Ogawa, Dirk Reinhardt, Marie-Laure Yaspo, Peter J Campbell, Irene Roberts, Stefan N Constantinescu, Paresh Vyas, Dirk Heckl, Jan-Henning Klusmann
Cancer cell 2019 Aug 12Myeloid 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. Copyright © 2019 Elsevier Inc. All rights reserved.
Maurice Labuhn, Kelly Perkins, Sören Matzk, Leila Varghese, Catherine Garnett, Elli Papaemmanuil, Marlen Metzner, Alison Kennedy, Vyacheslav Amstislavskiy, Thomas Risch, Raj Bhayadia, David Samulowski, David Cruz Hernandez, Bilyana Stoilova, Valentina Iotchkova, Udo Oppermann, Carina Scheer, Kenichi Yoshida, Adrian Schwarzer, Jeffrey W Taub, John D Crispino, Mitchell J Weiss, Yasuhide Hayashi, Takashi Taga, Etsuro Ito, Seishi Ogawa, Dirk Reinhardt, Marie-Laure Yaspo, Peter J Campbell, Irene Roberts, Stefan N Constantinescu, Paresh Vyas, Dirk Heckl, Jan-Henning Klusmann. Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome. Cancer cell. 2019 Aug 12;36(2):123-138.e10
PMID: 31303423
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