Mechanisms of progression of myeloid preleukemia to transformed myeloid leukemia in children with Down syndrome

Journal article

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.

Authors: Labuhn, M; Perkins, K; Matzk, S; Varghese, L; Garnett, C

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Cancer Cell
• Volume: 36
• Issue: 2
• Pages: 123-138.e10
• Publication date: 2019-07-11
• Acceptance date: 2019-06-11
• DOI: 10.1016/j.ccell.2019.06.007
• ISSN: 1535-6108
• Language: English
• Keywords: CRISPR screen; GATA1; Acute myeloid leukemia; preleukemia; cancer transformation; Down syndrome