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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; Iotchkova, Valentina; Oppermann, Udo; Scheer, Carina; Yoshida, Kenichi; Schwarzer, Adrian; Taub, Jeffrey W; Crispino, John D; Weiss, Mitchell J; Hayashi, Yasuhide; Taga, Takashi; Ito, Etsuro; Ogawa, Seishi; Reinhardt, Dirk; Yaspo, Marie-Laure; Campbell, Peter J; Roberts, Irene; Constantinescu, Stefan N; Vyas, Paresh; Heckl, Dirk; Klusmann, Jan-Henning.
Cancer Cell; 36(2): 123-138.e10, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31303423
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.
Selo DaSilva