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Cell Rep. 2016 May 10;15(6):1228-41. doi: 10.1016/j.celrep.2016.04.031. Epub 2016 Apr 28.

Systematic Cellular Disease Models Reveal Synergistic Interaction of Trisomy 21 and GATA1 Mutations in Hematopoietic Abnormalities.

Author information

1
Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
2
Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; Japan Society for the Promotion of Science, Chiyoda-ku, Tokyo 102-0083, Japan.
3
Laboratory of Gene Regulation, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
4
Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8562, Japan.
5
Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8526, Japan.
6
Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.
7
Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Shinjuku-ku, Tokyo 162-8666, Japan.
8
Department of Genome Biology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
9
Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan. Electronic address: ykitaba@ped.med.osaka-u.ac.jp.

Abstract

Chromosomal aneuploidy and specific gene mutations are recognized early hallmarks of many oncogenic processes. However, the net effect of these abnormalities has generally not been explored. We focused on transient myeloproliferative disorder (TMD) in Down syndrome, which is characteristically associated with somatic mutations in GATA1. To better understand functional interplay between trisomy 21 and GATA1 mutations in hematopoiesis, we constructed cellular disease models using human induced pluripotent stem cells (iPSCs) and genome-editing technologies. Comparative analysis of these engineered iPSCs demonstrated that trisomy 21 perturbed hematopoietic development through the enhanced production of early hematopoietic progenitors and the upregulation of mutated GATA1, resulting in the accelerated production of aberrantly differentiated cells. These effects were mediated by dosage alterations of RUNX1, ETS2, and ERG, which are located in a critical 4-Mb region of chromosome 21. Our study provides insight into the genetic synergy that contributes to multi-step leukemogenesis.

PMID:
27134169
DOI:
10.1016/j.celrep.2016.04.031
[Indexed for MEDLINE]
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