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

Maurice Labuhn, K. Perkins, Sören Matzk, L. Varghese, Catherine Garnett, Elli Papaemmanuil, Marlen Metzner, Alison Kennedy, Vyacheslav Amstislavskiy, Thomas Risch, Raj Bhayadia, D. Samulowski, David Cruz Hernandez, Bilyana Stoilova, Valentina Iotchkova, Udo Oppermann, Carina Scheer, Kenichi Yoshida, Adrian Schwarzer, Jeffrey TaubJohn D. Crispino, Mitchell J. Weiss, Asuhide Hayashi, Takashi Taga, Etsuro Ito, Seishi Ogawa, Dirk Reinhardt, Marie Laure Yaspo, Peter J. Campbell, I. Roberts, Stefan Constantinescu, Paresh Vyas*, Dirk Heckl, Jan Henning Klusmann

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

72 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)123-138.e10
JournalCancer cell
Issue number2
StatePublished - Aug 12 2019


  • Acute myeloid leukemia
  • CRISPR screen
  • Down syndrome
  • GATA1
  • cancer transformation
  • preleukemia

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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