Mechanisms of progression of myeloid preleukemia to transformed myeloid leukemia in children with Down syndrome Journal Article
| Authors: | Labuhn, M.; Perkins, K.; Matzk, S.; Varghese, L.; Garnett, C.; Papaemmanuil, E.; Metzner, M.; Kennedy, A.; Amstislavskiy, V.; Risch, T.; Bhayadia, R.; Samulowski, D.; Hernandez, D. C.; Stoilova, B.; Iotchkova, V.; Oppermann, U.; Scheer, C.; Yoshida, K.; Schwarzer, A.; Taub, J.; Crispino, J. D.; Weiss, M. J.; Hayashi, Y.; Taga, T.; Ito, E.; Ogawa, S.; Reinhardt, D.; Yaspo, M. L.; Campbell, P. J.; Roberts, I.; Constantinescu, S.; Vyas, P.; Heckl, D.; Klusmann, J. H. |
| Article Title: | Mechanisms of progression of myeloid preleukemia to transformed myeloid leukemia in children with Down syndrome |
| Abstract: | 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. Copyright © 2019 Elsevier Inc. All rights reserved. |
| Keywords: | down syndrome; acute myeloid leukemia; preleukemia; gata1; cancer transformation; crispr screen |
| Journal Title: | Cancer Cell |
| Volume: | 36 |
| Issue: | 2 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2019-08-12 |
| Start Page: | 123 |
| End Page: | 138.e10 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2019.06.007 |
| PUBMED: | 31303423 |
| PROVIDER: | scopus |
| PMCID: | PMC6863161 |
| DOI/URL: | |
| Notes: | Article -- Erratum issued, see DOI: 10.1016/j.ccell.2019.08.014 --Source: Scopus |
